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On July 3rd 2025, there was a man named Diogo Jota and his brother André Silva, Jota dies at 28 and Andre Silva dies at 30. Their place of death is in The Province of Zamora in Kingdom of Spain. They died because of Fast Lamborghini car crash on A-52 motorway at night because of getting to incorrect path, One day after Jota’s marriage. :’( . and he had recently undergone minor lung surgery in Porto, Portugal.
Artificial Intelligence (AI) is transforming industries worldwide by automating processes, improving efficiency, and enabling data-driven decision-making. From chatbots in banking to predictive analytics in healthcare and self-driving technology in transportation, AI has penetrated almost every sector. However, this rapid advancement has raised concerns about its impact on employment. On one hand, AI reduces the need for repetitive, manual, and routine jobs, leading to fears of large-scale job displacement. For example, automation in manufacturing has replaced many traditional labor-intensive roles, while AI-powered systems in customer service are gradually reducing the demand for human agents. This trend raises questions about unemployment, income inequality, and the future of work, particularly for those with low or medium skills who may find it difficult to adapt to new technologies.
On the other hand, AI also creates opportunities for innovation and employment in new areas. It has generated demand for professionals in data science, machine learning, robotics, and cybersecurity, opening up high-skilled jobs with attractive prospects. In addition, AI supports entrepreneurship by lowering costs and enhancing productivity, which indirectly fuels job creation. Governments and organizations must focus on reskilling and upskilling the workforce to prepare for an AI-driven economy. Educational reforms that emphasize digital literacy, problem-solving, and adaptability are essential to ensure workers remain relevant. Instead of perceiving AI solely as a threat, it should be viewed as a tool to complement human capabilities, allowing employees to focus on creativity, critical thinking, and emotional intelligence—areas where machines cannot easily replace humans. In conclusion, the impact of AI on employment depends on how societies manage the transition. With the right policies and training initiatives, AI can become a catalyst for inclusive growth rather than a cause of widespread job loss.
meteor 60 Swift-Tuttle. 133-year 60 orbit. part 60
yo ik ben quincy en ik scam mensen in steal a brainrot omdat ik zelf ben gescammed en ik gebruik fotos van brainrots die ik zelf geen eens heb
now I know that I can't make you stay but where's your heart but where's your heart but where's your
and I know there's nothing I can say to change that part to change that part to change so many bright lights that cast a shadow but can I speak well is it hard understanding I'm incomplete a life that's so demanding I get so weak a love that's so demanding I can't speak I am not afraid to keep on living I am not afraid to walk this world alone honey if you stay I'll be forgiven nothing you can say can stop me going home can you see my eyes are shining bright cause I'm out here on the other side of a jet black hotel mirror and I'm so weak is it hard understanding I'm incomplete a love that's so demanding I get weak I am not afraid to keep on living I am not afraid to walk this world alone honey if you stay I'll be forgiven nothing you can say can stop me going home I am not afraid to keep on living I am not afraid to walk this world alone honey if you stay I'll be forgiven nothing you can say can stop me going home these bright lights have always blinded me these bright lights have always blinded me I say I see you lying next to me with words I thought I'd never speak awake and unafraid asleep or dead cause I see you lying next to me with words I thought I'd never speak awake and unafraid asleep or dead cause I see you lying next to me with words I thought I'd never speak awake and unafraid asleep or dead cause I see you lying next to me with words I thought I'd never speak awake and unafraid asleep or dead I am not afraid to keep on living I am not afraid to walk this world alone or dead honey if you stay I'll be forgiven nothing you can say can stop me going home or dead I am not afraid to keep on living I am not afraid to walk this world alone or dead honey if you stay I'll be forgiven nothing you can say can stop me going home or dead I am not afraid to keep on living I am not afraid to walk this world alone or dead honey if you stay I'll be forgiven nothing you can say can stop me going home
Hi Mrs Robinson this is Gretchen Fisher from EZ pass Financial Dept. letting you now that you have missed a payment. We should have received your payment on August 8th 2025. we are informing you just in case you forgot. Let me know if you have any questions concerning this bill and I will be glad to help you. You can reach me at 443-866-6043 or you can send it to my email at Gretchenfisher510@yahoo.com. Thank you for being a valuable customer. Sincerely Gretchen Fisher
Yeah yeah yeah yeah yeah yeah yeah yeah yeah yeah yeah
Yeah yeah
Ra Rauw
Qué rico tener que desnudarte
No tengo que hacer mucho pa calentarte
Yo solo te miré y tú me entendiste
Cuando las gana insisten no se pueden aguantar
Baby, ya estamo solos
Nadie molesta
Cómo me miran tus ojos
La bellaquera revienta
Baby, hoy te voy a chingar
Y al oído va a gritarme
Que siempre me va a amar
Y que soy el dueño e toa tus parte
Hoy te voy a chingar
Voy a hacer que nunca pueda olvidarme
Tú y yo nos vamo a matar
Y hasta que te venga no voy a quitarme, yeah, yeah yeah
Esa lencería te queda divina
Íbamo pal cuarto y nos quedamo en la cocina
Perdí la cuenta de toa las venia
Pero ninguna como la primera en la piscina
Qué suerte que soy yo el que puede comerte
Qué hice para merecerte
Cada día que pasa lo que siento es má fuerte
Sólo quiero verte
Pero lo de nosotro, oh oh
No puede saberse, eh yeah
Siempre que te vas espero tu retorno
Nos vamo viral si sacamos la porno
Baby, ya estamo solos
Nadie molesta
Cómo me miran tus ojos
La bellaquera revienta
Baby, hoy te voy a chingar
Y al oído va a gritarme
Que siempre me va a amar
Y que soy el dueño e toa tus parte
Hoy te voy a chingar
Voy a hacer que nunca pueda olvidarme
Tú y yo nos vamo a matar
Y hasta que te venga no voy a quitarme, yeah, yeah yeah
Qué rico tener que desnudarte
No tengo que hacer mucho pa calentarte
Yo solo te miré y tú me entendiste
Cuando las gana insisten no se pueden aguantar
Baby, ya estamo solos
Nadie molesta
Cómo me miran tus ojos
La bellaquera revienta
Ey, ajá
Dice, Ra Rauw Alejandro
OMI
Hoy e' 2 catorce y
Esta canción la hice pa ti
Ella sabe quién e
Tú y yo nos vamo' a matar
Ey, ey
Duars Entertainment
Con los fuckin sensei
Quién sabe si mañana no te vuelvo a ver
Vamo a olvidarnos de lo correcto
Me quiero portar mal, te lo hago saber
La nota ya me hizo
El efecto
Porque tú me bailas así
Como si estuviéramo' en la cama
Qué rica te tienes que sentir
Desnudita sin nada
Dime cuándo nos vamos a ir
Que se nos acaba el tiempo
Ya te tienes que decidir
Si vienes o lo dejas para luego
Baby, hoy si que me puse yo pa ti
Porque así, freaky
Fue que tú me bailaste a mí
Moviéndote, twerking
De espalda te vi el g string
Im sorry si fresquito me puse al verte así
Erótico se puso
El encuentro entre tú y yo
Olvida si es lo correcto
Y el momento, vívetelo
Si a mí, mami, tú me permites fluir
Verás que fácil yo te llevo al éxtasis
No queda casi
Pa' que cierren esto aquí
Ya estamos horny
Qué es lo que hacemo' aquí
Porque tú me bailas así
Como si estuviéramo' en la cama
Qué rica te tienes que sentir
Desnudita sin nada
Dime cuándo nos vamos a ir
Que se nos acaba el tiempo
Ya te tienes que decidir
Si vienes o lo dejas para luego
Nadie está mirando
Y tampoco no se ve, hay poca luz
Mi mente pensando
Con ganas de saber cómo en la cama te ves tú
Si supieras lo que este efecto me provoca hacer
Experimentar contigo varias poses
Es que a mí todavía no me conoces
Como Calderón, esto es pa que te lo goces
Yo sabía que esto pasaría, que tú terminarías
Amanecida en mi cama
Después de esta noche to se olvida
Y si quieres otro día a cualquier hora me llamas
Yo sabía que esto pasaría, que tú terminarías
Amanecida en mi cama
Después de esta noche to se olvida
Y si quieres otro día a cualquier hora me llamas
Porque tú me bailas así
Como si estuviéramo' en la cama
Qué rica te tienes que sentir
Desnudita sin nada
Dime cuándo nos vamos a ir
Que se nos acaba el tiempo
Ya te tienes que decidir
Si vienes o lo dejas para luego
Quién sabe si mañana no te vuelvo a ver
Vamos a olvidarnos de lo correcto
Me quiero portar mal, te lo hago saber
La nota ya me hizo el efecto
Ra Rauw, ay
Ra Ra Rauw Alejandro
Chencho
Chencho
Checho Corleone, baby
Dímelo Niguel
Tun tun tun tun tun tun tun tun
Con Nais Gai, hey
Duran the Coach
Duars Entertainment
Con los Sensei
Dímelo Colla, ay
Pina Records
Steroid hormone synthesis
Steroid hormones are synthesized and secreted by the adrenal cortex, gonads, corpus luteum, and placenta. The steroid hormones are cortisol, aldosterone, estradiol and estriol, progesterone, testosterone, and 1,25-dihydroxycholecalciferol. All steroid hormones are derivatives of cholesterol, which is modified by removal or addition of side chains, hydroxylation, or aromatization of the steroid nucleus. The biosynthetic pathways for the adrenocortical hormones and for 1,25-dihydroxycholecalciferol are discussed in this chapter. The pathways for the sex steroid hormones are discussed in Chapter 10 .
Amine hormone synthesis
The amine hormones are catecholamines (epinephrine, norepinephrine, and dopamine) and thyroid hormones. The amine hormones are derivatives of the amino acid tyrosine. The biosynthetic pathway for catecholamines is discussed in Chapter 1 . The pathway for thyroid hormones is discussed in this chapter.
Hormones in the circulation
Once hormones are synthesized and secreted, they circulate in the blood either free or bound to proteins. Examples of hormones that are significantly bound in the circulation are thyroid hormones, steroid hormones, and insulin-like growth factors. Binding of hormones in the circulation has two functions: (1) to serve as a pool for the hormone and (2) to stabilize free hormone levels.
Regulation of hormone secretion
To maintain homeostasis, the secretion of hormones must be turned on and off as needed. Adjustments in secretory rates may be accomplished by neural mechanisms or by feedback mechanisms. Neural mechanisms are illustrated by the secretion of catecholamines, where preganglionic sympathetic nerves synapse on the adrenal medulla and, when stimulated, cause secretion of catecholamines into the circulation. Feedback mechanisms are more common than neural mechanisms. The term “feedback” means that some element of the physiologic response to a hormone “feeds back,” either directly or indirectly, on the endocrine gland that secreted the hormone, changing its secretion rate. Feedback can be negative or positive. Negative feedback is the more important and common mechanism for regulating hormone secretion; positive feedback is rare.
Negative feedback
The principles of negative feedback underlie the homeostatic regulation of virtually all organ systems. For example, in Chapter 4 , negative feedback is discussed in the regulation of arterial blood pressure in which small changes in blood pressure turn on, or activate, mechanisms that will restore blood pressure back to normal. A decrease in arterial blood pressure is detected by baroreceptors, which activate coordinated mechanisms that increase blood pressure. As blood pressure returns to normal, a disturbance is no longer sensed by the baroreceptors and those mechanisms previously activated will be turned off. The more sensitive the feedback mechanism, the smaller the “excursions” of blood pressure above or below normal.
In endocrine systems, negative feedback means that some feature of hormone action, directly or indirectly, inhibits further secretion of the hormone. Negative feedback loops are illustrated in Figure 9.3 . For illustrative purposes, the hypothalamus is shown in relation to the anterior pituitary, which is shown in relation to a peripheral endocrine gland. In the figure, the hypothalamus secretes a releasing hormone, which stimulates secretion of an anterior pituitary hormone. The anterior pituitary hormone then acts on a peripheral endocrine gland (e.g., the testis) to cause secretion of the hormone (e.g., testosterone), which acts on target tissues (e.g., skeletal muscle) to produce physiologic actions. The hormones “feed back” on the anterior pituitary and the hypothalamus to inhibit their hormonal secretions. Long-loop feedback means that the hormone feeds back all the way to the hypothalamic-pituitary axis. Short-loop feedback means that the anterior pituitary hormone feeds back on the hypothalamus to inhibit secretion of hypothalamic-releasing hormone. Not shown in the figure is a third possibility called ultrashort–loop feedback, in which the hypothalamic hormone inhibits its own secretion (e.g., growth hormone–releasing hormone [GHRH] inhibits GHRH secretion).
Two flow diagrams of feedback mechanism are shown. Negative feedback mechanism on the left shows steps as: 1. Hypothalamus stimulates anterior pituitary. 2. Stimulation of endocrine gland, testis for example, to secrete testosterone hormone, which acts on the target muscle tissue. 3. Anterior pituitary exerts a short-loop negative feedback on hypothalamus. 4. Hormone exerts a long-loop negative feedback on both anterior pituitary and hypothalamus. Positive feedback mechanism on the right shows steps as: 1. Hypothalamus stimulates anterior pituitary. 2. Stimulation of endocrine gland, ovary for example, to secrete estradiol hormone, which acts on the target tissue. 3. Hormone exerts a positive feedback on anterior pituitary.
Fig. 9.3
Negative and positive feedback mechanisms.
The hypothalamic-pituitary axis is used as an example in this illustration. Solid lines and plus signs (+) indicate stimulation; dashed lines and minus signs (−) indicate inhibition.
The net result of any version of negative feedback is that when hormone levels are judged (by their physiologic actions) to be adequate or high, further secretion of the hormone is inhibited. When hormone levels are judged to be inadequate or low, secretion of the hormone is stimulated.
There are other examples of negative feedback that do not utilize the hypothalamic-pituitary axis. For example, insulin regulates blood glucose concentration. In turn, insulin secretion is turned on or off by changes in the blood glucose concentration. Thus when blood glucose concentration is high, insulin secretion from the pancreas is turned on; insulin then acts on its target tissues (liver, muscle, and adipose) to decrease the blood glucose concentration back toward normal. When the glucose concentration is sensed as being low enough, insulin is no longer needed and its secretion is turned off.
Positive feedback
Positive feedback is uncommon. With positive feedback, some feature of hormone action causes more secretion of the hormone (see Fig. 9.3 ). When compared with negative feedback, which is self-limiting, positive feedback is self-augmenting. Although rare in biologic systems, when positive feedback does occur, it leads to an explosive event.
A nonhormonal example of positive feedback is the opening of nerve sodium (Na + ) channels during the upstroke of the action potential. Depolarization opens voltage-sensitive Na + channels and causes Na + entry into the cell, which leads to more depolarization and more Na + entry. This self-reinforcing process produces the rapid, explosive upstroke.
In hormonal systems, the primary example of positive feedback is the effect of estrogen on the secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by the anterior pituitary at the midpoint of the menstrual cycle. During the follicular phase of the menstrual cycle, the ovaries secrete estrogen, which acts on the anterior pituitary to produce a rapid burst of FSH and LH secretion. FSH and LH have two effects on the ovaries: ovulation and stimulation of estrogen secretion. Thus estrogen secreted from the ovaries acts on the anterior pituitary to cause secretion of FSH and LH, and these anterior pituitary hormones cause more estrogen secretion. In this example, the explosive event is the burst of FSH and LH that precedes ovulation.
A second example of hormonal positive feedback is oxytocin. Dilation of the cervix causes the posterior pituitary to secrete oxytocin. In turn, oxytocin stimulates uterine contraction, which causes further dilation of the cervix. In this example, the explosive event is parturition, the delivery of the fetus.
Regulation of hormone receptors
The previous section describes the mechanisms that regulate circulating levels of hormones, usually by negative feedback. Although circulating hormone levels are important, they are not the only determinant of the response of a target tissue. To respond, a target tissue must possess specific receptors that recognize the hormone. Those receptors are coupled to cellular mechanisms that produce the physiologic response. (The coupling mechanisms are discussed in the section on mechanisms of hormone action.)
The responsiveness of a target tissue to a hormone is expressed in the dose-response relationship in which the magnitude of response is correlated with hormone concentration. As the hormone concentration increases, the response usually increases and then levels off. Sensitivity is defined as the hormone concentration that produces 50% of the maximal response. If more hormone is required to produce 50% of the maximal response, then there has been a decrease in sensitivity of the target tissue. If less hormone is required, there has been an increase in sensitivity of the target tissue.
The responsiveness or sensitivity of a target tissue can be changed in one of two ways: by changing the number of receptors or by changing the affinity of the receptors for the hormone. The greater the number of receptors for a hormone, the greater the maximal response. The higher the affinity of the receptor for the hormone, the greater the likelihood of a response.
A change in the number or affinity of receptors is called down-regulation or up-regulation. Down-regulation means that the number of receptors or the affinity of the receptors for the hormone has decreased. Up-regulation means that the number or the affinity of the receptors has increased. Hormones may down-regulate or up-regulate their own receptors in target tissues and even may regulate receptors for other hormones.
Down-regulation
Down-regulation is a mechanism in which a hormone decreases the number or affinity of its receptors in a target tissue. Down-regulation may occur by decreasing the synthesis of new receptors, by increasing the degradation of existing receptors, or by inactivating receptors. The purpose of down-regulation is to reduce the sensitivity of the target tissue when hormone levels are high for an extended period of time. As down-regulation occurs, the response to hormone declines, although hormone levels remain high. An example of down-regulation is the effect of progesterone on its own receptor in the uterus (see Chapter 10 ).
Down-regulation can also refer to a hormone’s effect on receptors for other related hormones. This type of down-regulation also is illustrated by progesterone. In the uterus, progesterone down-regulates its own receptor and down-regulates the receptors for estrogen. A second example of this type of down-regulation is seen in the thyroid system: Triiodothyronine, or T 3 , decreases the sensitivity of thyrotropin-releasing hormone (TRH) receptors in the anterior pituitary. The overall effect is that chronically high levels of T 3 reduce the overall responsiveness of the hypothalamic-pituitary-thyroid axis.
Up-regulation
Up-regulation of receptors is a mechanism in which a hormone increases the number or affinity of its receptors. Up-regulation may occur by increasing synthesis of new receptors, decreasing degradation of existing receptors, or activating receptors. For example, prolactin increases the number of its receptors in the breast, growth hormone increases the number of its receptors in skeletal muscle and liver, and estrogen increases the number of its receptors in the uterus.
A hormone also can up-regulate the receptors for other hormones. For example, estrogen not only up-regulates its own receptor in the uterus, but it also up-regulates the receptors for LH in the ovaries.
Mechanisms of hormone action and second messengers
Hormone actions on target cells begin when the hormone binds to a membrane receptor, forming a hormone-receptor complex. In many hormonal systems, the hormone-receptor complex is coupled to effector proteins by guanosine triphosphate (GTP)–binding proteins (G proteins). The effector proteins usually are enzymes, either adenylyl cyclase or phospholipase C. When the effector proteins are activated, a second messenger, either cyclic adenosine monophosphate (cAMP) or inositol 1,4,5-triphosphate (IP 3 ), is produced, which amplifies the original hormonal signal and orchestrates the physiologic actions.
The major mechanisms of hormone action on target cells are the adenylyl cyclase mechanism, in which cAMP is the second messenger; the phospholipase C mechanism, in which IP 3 /Ca 2+ is the second messenger; and the steroid hormone mechanism. In addition, insulin and insulin-like growth factors (IGFs) act on their target cells through a tyrosine kinase mechanism. Finally, several hormones activate guanylate cyclase, in which cyclic guanosine monophosphate (cyclic GMP, or cGMP) is the second messenger. The mechanisms of action of the major hormones are summarized in Table 9.3 .
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TABLE 9.3
Mechanisms of Hormone Action
Adenylyl Cyclase Mechanism (cAMP) Phospholipase C Mechanism (IP 3 /Ca 2+ ) Steroid Hormone Mechanism Tyrosine Kinase Mechanism Guanylate Cyclase Mechanism (cGMP)
ACTH
LH
FSH
TSH
ADH (V 2 receptor)
HCG
MSH
CRH
Calcitonin
PTH
Glucagon
β 1 and β 2 receptors
GnRH
TRH
GHRH
Angiotensin II
ADH (V 1 receptor)
Oxytocin
α 1 Receptors
Glucocorticoids
Estrogen
Progesterone
Testosterone
Aldosterone
1,25- Dihydroxycholecalciferol
Thyroid hormones
Insulin
IGF-1
Growth hormone
Prolactin
Atrial natriuretic peptide (ANP)
Nitric oxide (NO)
cAMP, Cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; IP 3 , inositol 1,4,5-triphosphate.
G proteins
G proteins are discussed in Chapter 2 in the context of autonomic receptors. Briefly, G proteins are a family of membrane-bound proteins that couple hormone receptors to effector enzymes (e.g., adenylyl cyclase). Thus G proteins serve as “molecular switches” that decide whether the hormone action can proceed.
At the molecular level, G proteins are heterotrimeric proteins (i.e., they have three subunits). The three subunits are designated alpha (α), beta (β), and gamma (γ). The α subunit can bind either guanosine diphosphate (GDP) or GTP, and it contains GTPase activity. When GDP is bound to the α subunit, the G protein is inactive; when GTP is bound, the G protein is active and can perform its coupling function. Guanosine nucleotide- releasing factors (GRFs) facilitate dissociation of GDP so that GTP binds more rapidly, whereas GTPase-activating factors (GAPs) facilitate hydrolysis of GTP. Thus the relative activity of GRFs and GAPs influences the overall rate of G protein activation.
G proteins can be either stimulatory or inhibitory and are called, accordingly, G s or G i . Stimulatory or inhibitory activity resides in the α subunit (α s or α i ). Thus when GTP is bound to the α s subunit of a G s protein, the G s protein stimulates the effector enzyme (e.g., adenylyl cyclase). When GTP is bound to the α i subunit of a G i protein, the G i protein inhibits the effector enzyme.
Adenylyl cyclase mechanism
The adenylyl cyclase/cAMP mechanism is utilized by many hormonal systems (see Table 9.3 ). This mechanism involves binding of a hormone to a receptor, coupling by a G s or G i protein, and then activating or inhibiting adenylyl cyclase, leading to increases or decreases in intracellular cAMP. cAMP, the second messenger, then amplifies the hormonal signal to produce the final physiologic actions.
The steps in the adenylyl cyclase/cAMP mechanism are shown in Figure 9.4 . In this example, the hormone utilizes a G s protein (rather than a G i protein). The receptor–G s –adenylyl cyclase complex is embedded in the cell membrane. When no hormone is bound to the receptor, the α s subunit of the G s protein binds GDP. In this configuration, the G s protein is inactive. When hormone binds to its receptor, the following steps (see Fig. 9.4 ) occur:
1.
Hormone binds to its receptor in the cell membrane, producing a conformational change in the α s subunit (Step 1), which produces two changes: GDP is released from the α s subunit and is replaced by GTP, and the α s subunit detaches from the G s protein (Step 2).
2.
The α s -GTP complex migrates within the cell membrane and binds to and activates adenylyl cyclase (Step 3). Activated adenylyl cyclase catalyzes the conversion of adenosine triphosphate (ATP) to cAMP, which serves as the second messenger (Step 4). Although not shown, intrinsic GTPase activity in the G protein converts GTP back to GDP, and the α s subunit returns to its inactive state.
3.
cAMP, via a series of steps involving activation of protein kinase A, phosphorylates serine and threonine groups on intracellular proteins (Steps 5 and 6). These phosphorylated proteins then execute the final physiologic actions (Step 7).
4.
Intracellular cAMP is degraded to an inactive metabolite, 5′ adenosine monophosphate (5′ AMP), by the enzyme phosphodiesterase, thereby turning off the action of the second messenger.
In inactive phase, no hormone is bound to the receptor, the alpha s subunit of G s protein binds to G D P, and the adenylyl cyclase remains inactive. In active phase, when hormone is bound to the receptor, the alpha s subunit of G s protein binds to G T P, the alpha s G T P complex binds to adenylyl cyclase, converting A T P to c A M P. c A M P is converted to inactive 5 A M P by phosphodiesterase enzyme. c A M P activates protein kinase A, leading to phosphorylation of proteins, which initiates physiologic actions.
Fig. 9.4
Steps involved in the adenylyl cyclase (cAMP) mechanism of action.
See the text for an explanation of the circled numbers. AMP, Adenosine monophosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; GDP, guanosine diphosphate; GTP, guanosine triphosphate.
Phospholipase C mechanism
Hormones that utilize the phospholipase C (IP 3 /Ca 2+ ) mechanism also are listed in Table 9.3 . The mechanism involves binding of hormone to a receptor and coupling via a G q protein to phospholipase C. Intracellular levels of IP 3 and Ca 2+ are increased, producing the final physiologic actions. The steps in the phospholipase C (IP 3 /Ca 2+ ) mechanism are shown in Figure 9.5 .
In inactive phase, no hormone is bound to the receptor, the alpha q subunit of G q protein binds to G D P, and the phospholipase C remains inactive. In active phase, when hormone is bound to the receptor, the alpha q subunit of G q protein binds to G T P, the alpha q G T P complex binds to phospholipase C, which catalyzes the conversion of P I P 2 to diacylglycerol and I P 3. I P 3 results in release of calcium from E R or S R. Both calcium and diacylglycerol stimulate protein kinase C, thereby initiating physiologic actions.
Fig. 9.5
Steps involved in the phospholipase C (IP 3 /Ca 2+ ) mechanism of action.
See the text for an explanation of the circled numbers. ER, Endoplasmic reticulum; GDP, guanosine diphosphate; GTP, guanosine triphosphate; IP 3 , inositol 1,4,5-triphosphate; PIP 2 , phosphatidylinositol 4,5-diphosphate; SR, sarcoplasmic reticulum.
The receptor–G q –phospholipase C complex is embedded in the cell membrane. With no hormone bound to the receptor, the α q subunit binds GDP. In this configuration, the G q protein is inactive. When the hormone binds to the receptor, G q is activated, which activates phospholipase C, in the following steps (see Fig. 9.5 ):
1.
Hormone binds to its receptor in the cell membrane, producing a conformational change in the α q subunit (Step 1). GDP is released from the α q subunit and is replaced by GTP, and the α q subunit detaches from the G q protein (Step 2).
2.
The α q -GTP complex migrates within the cell membrane and binds to and activates phospholipase C (Step 3). Activated phospholipase C catalyzes the liberation of diacylglycerol and IP 3 from phosphatidylinositol 4,5-diphosphate (PIP 2 ), a membrane phospholipid (Step 4). The IP 3 generated causes the release of Ca 2+ from intracellular stores in the endoplasmic or sarcoplasmic reticulum, resulting in an increase in intracellular Ca 2+ concentration (Step 5).
3.
Together, Ca 2+ and diacylglycerol activate protein kinase C (Step 6), which phosphorylates proteins and produces the final physiologic actions (Step 7).
Catalytic receptor mechanisms
Some hormones bind to cell surface receptors that have, or are associated with, enzymatic activity on the intracellular side of the cell membrane. These so-called catalytic receptors include guanylyl cyclase, serine/threonine kinases, tyrosine kinases, and tyrosine kinase–associated receptors. Guanylyl cyclase catalyzes the generation of cGMP from GTP. The kinases phosphorylate serine, threonine, or tyrosine on proteins and thus add negative charge in the form of the phosphate group; phosphorylation of target proteins results in conformational changes that are responsible for the hormone’s physiologic actions.
Guanylyl cyclase
Hormones acting through the guanylyl cyclase mechanism are also listed in Table 9.3 . Atrial natriuretic peptide (ANP) and related natriuretic peptides act through a receptor guanylyl cyclase mechanism as follows (see Chapters 4 and 6 ). The extracellular domain of the receptor has a binding site for ANP, while the intracellular domain of the receptor has guanylyl cyclase activity. Binding of ANP causes activation of guanylyl cyclase and conversion of GTP to cGMP. cGMP then activates cGMP-dependent kinase, which phosphorylates the proteins responsible for ANP’s physiologic actions.
Nitric oxide (NO) acts through a cytosolic guanylyl cyclase as follows (see Chapter 4 ). NO synthase in vascular endothelial cells cleaves arginine into citrulline and NO. The just-synthesized NO diffuses out of the endothelial cells into nearby vascular smooth muscle cells, where it binds to and activates soluble, or cytosolic, guanylyl cyclase. GTP is converted to cGMP, which relaxes vascular smooth muscle.
Serine/threonine kinases
As previously discussed, numerous hormones utilize G protein–linked receptors as part of the adenylyl cyclase and phospholipase C mechanisms (see Table 9.3 ). In these mechanisms, the cascade of events ultimately activates protein kinase A or protein kinase C, respectively. The activated kinases then phosphorylate serine and threonine moieties on proteins that execute the hormone’s physiologic actions. In addition, Ca 2+ -calmodulin-dependent protein kinase (CaMK) and mitogen-activated protein kinases (MAPKs) phosphorylate serine and threonine in the cascade of events leading to their biologic actions.
Tyrosine kinases
Tyrosine kinases phosphorylate tyrosine moieties on proteins and fall in two major categories. Receptor tyrosine kinases have intrinsic tyrosine kinase activity within the receptor molecule. Tyrosine kinase–associated receptors do not have intrinsic tyrosine kinase activity but associate noncovalently with proteins that do ( Fig. 9.6 ).
♦
Receptor tyrosine kinases have an extracellular binding domain that binds the hormone or ligand, a hydrophobic transmembrane domain, and an intracellular domain that contains tyrosine kinase activity. When activated by hormone or ligand, the intrinsic tyrosine kinase phosphorylates itself and other proteins.
One type of receptor tyrosine kinase is a monomer (e.g., nerve growth factor [NGF] and epidermal growth factor receptors, see Fig. 9.6 A). In this monomeric type, binding of ligand to the extracellular domain results in dimerization of the receptor, activation of intrinsic tyrosine kinase, and phosphorylation of tyrosine moieties on itself and other proteins, leading to its physiologic actions.
Another type of receptor tyrosine kinase is already a dimer (e.g., insulin and insulin-like growth factor [IGF] receptors, see Fig. 9.6 B). In this dimeric type, binding of the ligand (e.g., insulin) activates intrinsic tyrosine kinase and leads to phosphorylation of itself and other proteins and ultimately the hormone’s physiologic actions. The mechanism of the insulin receptor is also discussed later in the chapter.
♦
Tyrosine kinase–associated receptors (e.g., growth hormone receptors, see Fig. 9.6 C) also have an extracellular domain, a hydrophobic transmembrane domain, and an intracellular domain. However, unlike the receptor tyrosine kinases, the intracellular domain does not have tyrosine kinase activity but is noncovalently “associated” with tyrosine kinase such as those in the Janus kinase family ( JAK, Janus family of receptor-associated tyrosine kinase, or “just another kinase”). Hormone binds to the extracellular domain, leading to receptor dimerization and activation of tyrosine kinase in the associated protein (e.g., JAK). The associated tyrosine kinase phosphorylates tyrosine moieties on itself, the hormone receptor, and other proteins. Downstream targets of JAK include members of the STAT (signal transducers and activators of transcription) family, which cause transcription of mRNAs and ultimately new proteins involved in the hormone’s physiologic actions.
Tyrosine kinase receptors traverse through the cell membrane with tyrosine kinase activity at the intracellular level. Nerve growth factor binds to the nerve growth factor receptors on the extracellular side. Insulin binds to the alpha subunits of the insulin receptors present on the extracellular side. The two alpha subunits are connected by a disulphide bond and each alpha subunit is also connected to the transmembrane beta subunit by a disulphide bond. Tyrosine kinase-associated receptors traverse through the cell membrane with J A K tyrosine kinase activity at the intracellular level. Growth hormone binds to the growth hormone receptors on the extracellular side.
Fig. 9.6
Tyrosine kinase receptors.
Nerve growth factor (A) and insulin (B) utilize receptor tyrosine kinases that have intrinsic tyrosine kinase activity. Growth hormone (C) utilizes a tyrosine kinase–associated receptor. JAK, Janus family of receptor-associated tyrosine kinase; NGF, nerve growth factor.
Steroid and thyroid hormone mechanism
Steroid hormones and thyroid hormones have the same mechanism of action. In contrast to the adenylyl cyclase and phospholipase C mechanisms utilized by peptide hormones and involving cell membrane receptors and generation of intracellular second messengers, the steroid hormone mechanism involves binding to cytosolic (or nuclear) receptors ( Fig. 9.7 ) that initiate DNA transcription and synthesis of new proteins. In further contrast to peptide hormones, which act quickly on their target cells (within minutes), steroid hormones act slowly (taking hours).
A steroid hormone receptor has domain A and B, D N A-binding domain C with two zinc molecules, domain D, hormone-binding dimerization domain E, and domain F. N H 2 is attached to the left end and C O O H is attached to the right.
Fig. 9.7
Structure of cytosolic (or nuclear) steroid hormone receptor.
Letters A–F represent the six domains of the receptor.
The steps in the steroid hormone mechanism (shown in Fig. 9.8 ) are described as follows:
1.
The steroid hormone diffuses across the cell membrane and enters its target cell (Step 1), where it binds to a specific receptor protein (Step 2) that is located in either the cytosol (as shown in Fig. 9.8 ) or nucleus. Steroid hormone receptors are monomeric phosphoproteins that are part of a gene superfamily of intracellular receptors. Each receptor has six domains (see Fig. 9.7 ). The steroid hormone binds in the E domain located near the C terminus. The central C domain is highly conserved among different steroid hormone receptors, has two zinc fingers, and is responsible for DNA binding. With hormone bound, the receptor undergoes a conformational change and the activated hormone- receptor complex enters the nucleus of the target cell.
2.
The hormone-receptor complex dimerizes and binds (at its C domain) via the zinc fingers to specific DNA sequences, called steroid-responsive elements (SREs) located in the 5′ region of target genes (Step 3).
3.
The hormone-receptor complex has now become a transcription factor that regulates the rate of transcription of that gene (Step 4). New messenger RNA (mRNA) is transcribed (Step 5), leaves the nucleus (Step 6), and is translated to new proteins (Step 7) that have specific physiologic actions (Step 8). The nature of the new proteins is specific to the hormone and accounts for the specificity of the hormone’s actions. For example, 1,25-dihydroxycholecalciferol induces the synthesis of a Ca 2+ -binding protein that promotes Ca 2+ absorption from the intestine; aldosterone induces synthesis of Na + channels (ENaC) in the renal principal cells that promote Na + reabsorption in the kidney; and testosterone induces synthesis of skeletal muscle proteins.
A flow diagram of steroid hormone mechanism is as follows: 1. Steroid hormone crosses the cell membrane and enters cytosol. 2. Binds to domain C of cytoplasmic or nuclear receptor. 3. The hormone-receptor complex enters the nucleus, undergoes dimerization, and then binds to S R E of a D N A sequence. 4. Transcription to form m R N A. 5. The m R N A leaves the nucleus and enters cytosol to undergo translation and form new proteins, initiating physiologic actions.
Fig. 9.8
Steps involved in the steroid hormone mechanism of action.
See the text for an explanation of the circled numbers. mRNA, Messenger ribonucleic acid; SREs, steroid-responsive elements.
Hypothalamic-pituitary relationships
The hypothalamus and pituitary gland function in a coordinated fashion to orchestrate many of the endocrine systems. The hypothalamic-pituitary unit regulates the functions of the thyroid, adrenal, and reproductive glands and also controls growth, milk production and ejection, and osmoregulation. It is important to visualize the anatomic relationships between the hypothalamus and the pituitary because these relationships underlie the functional connections between the glands.
The pituitary gland, which also is called the hypophysis, consists of a posterior lobe and an anterior lobe. The posterior lobe (or posterior pituitary) is also called the neurohypophysis. The anterior lobe (or anterior pituitary) is also called the adenohypophysis. The hypothalamus is connected to the pituitary gland by a thin stalk called the infundibulum. Functionally, the hypothalamus controls the pituitary gland by both neural and hormonal mechanisms ( Fig. 9.9 ).
An illustration of hypothalamus and anterior pituitary is shown. Hypothalamus stimulates the posterior lobe of pituitary to secrete posterior lobe hormones, A D H for example, which reaches the target tissues like kidney. The hypothalamus secretes hypothalamic-releasing and release-inhibiting hormones, T R H for example, which travels through hypothalamic-hypophysial portal vessels to anterior lobe of pituitary. This stimulates the secretion of anterior lobe hormones like T S H, which reaches the target tissues like thyroid gland.
Fig. 9.9
Schematic figure showing the relationship between the hypothalamus and the posterior and anterior lobes of the pituitary gland.
Pink circles are posterior pituitary hormones; yellow circles are hypothalamic hormones; triangles are anterior pituitary hormones. ADH, Antidiuretic hormone; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.
Relationship of the hypothalamus to the posterior pituitary
The posterior lobe of the pituitary gland is derived from neural tissue. It secretes two peptide hormones, antidiuretic hormone (ADH) and oxytocin, which act on their respective target tissues—the kidney and arterioles (ADH) and the breast and uterus (oxytocin).
The connections between the hypothalamus and the posterior lobe of the pituitary are neural. In fact, the posterior pituitary is a collection of nerve axons whose cell bodies are located in the hypothalamus. Thus the hormones secreted by the posterior lobe (ADH and oxytocin) are actually neuropeptides; in other words, they are peptides released from neurons.
The cell bodies of ADH- and oxytocin-secreting neurons are located in supraoptic and paraventricular nuclei within the hypothalamus. Although both hormones are synthesized in both nuclei, ADH is primarily associated with supraoptic nuclei and oxytocin is primarily associated with paraventricular nuclei.
Once synthesized in the cell bodies, the hormones (i.e., neuropeptides) are transported down the axons in neurosecretory vesicles and stored in bulbous nerve terminals in the posterior pituitary. When the cell body is stimulated, the neurosecretory vesicles are released from the nerve terminals by exocytosis and the secreted hormone enters nearby fenestrated capillaries. Venous blood from the posterior pituitary enters the systemic circulation, which delivers the hormones to their target tissues.
In summary, the relationship between the hypothalamus and the posterior pituitary is straightforward— a hormone-secreting neuron has its cell body in the hypothalamus and its axons in the posterior lobe of the pituitary.
Relationship of the hypothalamus to the anterior pituitary
The anterior lobe of the pituitary gland is derived from primitive foregut. Unlike the posterior lobe, which is neural tissue, the anterior lobe is primarily a collection of endocrine cells. The anterior pituitary secretes six peptide hormones: thyroid-stimulating hormone (TSH), FSH, LH, growth hormone, prolactin, and adrenocorticotropic hormone (ACTH).
The nature of the relationship between the hypothalamus and the anterior pituitary is both neural and endocrine (in contrast to the posterior lobe, which is only neural). The hypothalamus and anterior pituitary are linked directly by the hypothalamic-hypophysial portal blood vessels, which provide most of the blood supply of the anterior lobe.
There are both long and short hypophysial portal vessels, which are distinguished as follows: Arterial blood is delivered to the hypothalamus via the superior hypophysial arteries, which distribute the blood in a capillary network in the median eminence, called the primary capillary plexuses. These primary capillary plexuses converge to form the long hypophysial portal vessels, which travel down the infundibulum to deliver hypothalamic venous blood to the anterior lobe of the pituitary. A parallel capillary plexus forms from the inferior hypophysial arteries in the lower portion of the infundibular stem. These capillaries converge to form the short hypophysial portal vessels, which deliver blood to the anterior lobe of the pituitary. In summary, the blood supply of the anterior pituitary differs from that of other organs: Most of its blood supply is venous blood from the hypothalamus, supplied by the long and short hypophysial portal vessels.
There are two important physiologic implications of the portal blood supply to the anterior lobe of the pituitary: (1) The hypothalamic hormones can be delivered to the anterior pituitary directly and in high concentration, and (2) the hypothalamic hormones do not appear in the systemic circulation in high concentrations. The cells of the anterior pituitary, therefore, are the only cells in the body to receive high concentrations of the hypothalamic hormones.
The functional connections between the hypothalamus and the anterior lobe of the pituitary now can be understood in the context of the anatomic connections. Hypothalamic-releasing hormones and release-inhibiting hormones are synthesized in the cell bodies of hypothalamic neurons and travel down the axons of these neurons to the median eminence of the hypothalamus. Upon stimulation of these neurons, the hormones are secreted into the surrounding hypothalamic tissue and enter the nearby capillary plexus. The blood from these capillaries (now venous blood) drains into the hypophysial portal vessels and is delivered directly to the anterior lobe of the pituitary. There, the hypothalamic hormones act on the cells of the anterior lobe, where they stimulate or inhibit the release of the anterior pituitary hormones. The anterior pituitary hormones then enter the systemic circulation, which delivers them to their target tissues.
The hypothalamic-anterior pituitary relationship can be illustrated by considering the TRH–TSH–thyroid hormone system. TRH is synthesized in hypothalamic neurons and secreted in the median eminence of the hypothalamus, where it enters capillaries and then hypophysial portal vessels. It is delivered in this portal blood to the anterior lobe of the pituitary, where it stimulates TSH secretion. TSH enters the systemic circulation and is delivered to its target tissue, the thyroid gland, where it stimulates secretion of thyroid hormones.
Anterior lobe hormones
Six major hormones are secreted by the anterior lobe of the pituitary: TSH, FSH, LH, ACTH, growth hormone, and prolactin. Each hormone is secreted by a different cell type (except FSH and LH, which are secreted by the same cell type). The cell types are denoted by the suffix “troph,” meaning nutritive. Thus TSH is secreted by thyrotrophs (5%), FSH and LH by gonadotrophs (15%), ACTH by corticotrophs (15%), growth hormone by somatotrophs (20%), and prolactin by lactotrophs (15%). (The percentages give the representation of each cell type in the anterior pituitary gland.)
Each of the anterior pituitary hormones is a peptide or polypeptide. As described, the synthesis of peptide hormones includes the following steps: transcription of DNA to mRNA in the nucleus; translation of mRNA to a preprohormone on the ribosomes; and post-translational modification of the preprohormone on the endoplasmic reticulum and the Golgi apparatus to produce the final hormone. The hormone is stored in membrane-bound secretory granules for subsequent release. When the anterior pituitary is stimulated by a hypothalamic-releasing hormone or a release-inhibiting hormone (e.g., thyrotrophs are stimulated by TRH to secrete TSH), there is exocytosis of the secretory granules; the anterior pituitary hormone (e.g., TSH) enters capillary blood and is delivered by the systemic circulation to the target tissue (e.g., thyroid gland).
The hormones of the anterior lobe are organized in “families” according to their structural and functional homology. TSH, FSH, and LH are structurally related and constitute one family, ACTH is part of a second family, and growth hormone and prolactin constitute a third family.
TSH, FSH, LH, and ACTH are discussed briefly in this section and later in the chapter in the context of their actions. (TSH is discussed within the context of the thyroid gland. ACTH is discussed in the context of the adrenal cortex. FSH and LH are discussed in Chapter 10 with male and female reproductive physiology.) Growth hormone and prolactin are discussed in this section.
TSH, FSH, and LH family
TSH, FSH, and LH are all glycoproteins with sugar moieties covalently linked to asparagine residues in their polypeptide chains. Each hormone consists of two subunits, α and β, which are not covalently linked; none of the subunits alone is biologically active. The α subunits of TSH, FSH, and LH are identical and are synthesized from the same mRNA. The β subunits for each hormone are different and therefore confer the biologic specificity (although the β subunits have a high degree of homology among the different hormones). During the biosynthetic process, pairing of the α and β subunits begins in the endoplasmic reticulum and continues in the Golgi apparatus. In the secretory granules, the paired molecules are refolded into more stable forms prior to secretion.
The placental hormone human chorionic gonadotropin (HCG) is structurally related to the TSH-FSH-LH family. Thus HCG is a glycoprotein with the identical α chain and its own β chain, which confers its biologic specificity.
ACTH family
The ACTH family is derived from a single precursor, pro-opiomelanocortin (POMC). The ACTH family includes ACTH, γ- and β-lipotropin, β-endorphin, and melanocyte-stimulating hormone (MSH). ACTH is the only hormone in this family with well-established physiologic actions in humans. MSH is involved in pigmentation in lower vertebrates and has some activity in humans. β-Endorphin is an endogenous opiate.
The preprohormone for this group, prepro-opiomelanocortin, is transcribed from a single gene. The signal peptide is cleaved in the endoplasmic reticulum, yielding POMC, the precursor to the ACTH family. Endopeptidases then hydrolyze peptide bonds in POMC and intermediates to produce the members of the ACTH family ( Fig. 9.10 ). The anterior pituitary in humans produces mainly ACTH, γ-lipotropin, and β-endorphin.
P O M C has four fragments; first two fragments separate as A C T H intermediate and the next two fragments separate as beta lipoprotein. The A C T H intermediate separates into a fragment containing gamma M S H and A C T H fragment containing alpha M S H. The beta lipoprotein fragment separates into beta endorphin and gamma lipoprotein containing beta M S H.
Fig. 9.10
The hormones derived from pro-opiomelanocortin (POMC) .
The fragment contains γ-MSH; ACTH contains α-MSH; and γ-lipotropin contains β-MSH. ACTH, Adrenocorticotropic hormone; MSH, melanocyte-stimulating hormone.
It is noteworthy that MSH activity is found in POMC and in several of its products: The “fragment,” which is left over from hydrolysis of the ACTH intermediate, contains γ-MSH; ACTH contains α-MSH; and γ-lipotropin contains β-MSH. These MSH-containing fragments can cause skin pigmentation in humans if their blood levels are increased. For example, in Addison disease (primary adrenal insufficiency), POMC and ACTH levels are increased by negative feedback. Because POMC and ACTH contain MSH activity, skin pigmentation is a symptom of this disorder.
Growth hormone
Growth hormone is secreted throughout life. It is the single most important hormone for normal growth to adult stature. Considering the broad nature of this task (growth), it is not surprising that growth hormone has profound effects on protein, carbohydrate, and fat metabolism.
Chemistry of growth hormone
Growth hormone is synthesized in the somatotrophs of the anterior lobe of the pituitary and also is called somatotropin or somatotropic hormone. Human growth hormone contains 191 amino acids in a straight-chain polypeptide with 2 internal disulfide bridges. The gene for growth hormone is a member of a family of genes for related peptides, prolactin, and human placental lactogen. The synthesis of growth hormone is stimulated by GHRH, its hypothalamic-releasing hormone.
Human growth hormone is structurally similar to prolactin, which is synthesized by lactotrophs in the anterior lobe, and to human placental lactogen, which is synthesized in the placenta. Prolactin, a 198–amino acid straight-chain polypeptide with 3 disulfide bridges, has 75% homology with growth hormone. Human placental lactogen, a 191–amino acid straight-chain polypeptide with 2 disulfide bridges, has 80% homology.
Regulation of growth hormone secretion
Growth hormone is secreted in a pulsatile pattern, with bursts of secretion occurring approximately every 2 hours. The largest secretory burst occurs within 1 hour of falling asleep (during sleep stages III and IV). The bursting pattern, in terms of both frequency and magnitude, is affected by several agents that alter the overall level of growth hormone secretion ( Table 9.4 ).
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TABLE 9.4
Factors Affecting Growth Hormone Secretion
Stimulatory Factors Inhibitory Factors
Decreased glucose concentration
Decreased free fatty acid concentration
Arginine
Fasting or starvation
Hormones of puberty (estrogen, testosterone)
Exercise
Stress
Stage III and IV sleep
α-Adrenergic agonists
Increased glucose concentration
Increased free fatty acid concentration
Obesity
Senescence
Somatostatin
Somatomedins
Growth hormone
β-Adrenergic agonists
Pregnancy
Growth hormone secretory rates are not constant over a lifetime. The rate of secretion increases steadily from birth into early childhood. During childhood, secretion remains relatively stable. At puberty, there is an enormous secretory burst, induced in females by estrogen and in males by testosterone. The high pubertal levels of growth hormone are associated with both increased frequency and increased magnitude of the secretory pulses and are responsible for the growth spurt of puberty. After puberty, the rate of growth hormone secretion declines to a stable level. Finally, in senescence, growth hormone secretory rates and pulsatility decline to their lowest levels.
The major factors that alter growth hormone secretion are summarized in Table 9.4 . Hypoglycemia (a decrease in blood glucose concentration) and starvation are potent stimuli for growth hormone secretion. Other stimuli for secretion are exercise and various forms of stress including trauma, fever, and anesthesia. The highest rates of growth hormone secretion occur during puberty, and the lowest rates occur in senescence.
Regulation of growth hormone secretion is illustrated in Figure 9.11 , which shows the relationship between the hypothalamus, the anterior lobe of the pituitary, and the target tissues for growth hormone. Secretion of growth hormone by the anterior pituitary is controlled by two pathways from the hypothalamus, one stimulatory (GHRH) and the other inhibitory (somatostatin, also known as somatotropin release–inhibiting factor [SRIF]).
♦
GHRH acts directly on somatotrophs of the anterior pituitary to induce transcription of the growth hormone gene and thereby to stimulate both synthesis and secretion of growth hormone. In initiating its action on the somatotroph, GHRH binds to a membrane receptor, which is coupled through a G s protein to both adenylyl cyclase and phospholipase C. Thus GHRH stimulates growth hormone secretion by utilizing both cAMP and IP 3 /Ca 2+ as second messengers.
♦
Somatostatin (somatotropin release–inhibiting hormone [SRIF]) is also secreted by the hypothalamus and acts on the somatotrophs to inhibit growth hormone secretion. Somatostatin inhibits growth hormone secretion by blocking the action of GHRH on the somatotroph. Somatostatin binds to its own membrane receptor, which is coupled to adenylyl cyclase by a G i protein, inhibiting the generation of cAMP and decreasing growth hormone secretion.
A flow diagram lists the following steps: 1. Hypothalamus secretes G H R H. 2. Stimulation of anterior pituitary to release growth hormone, which acts on target tissues. 3. Somatostatin release-inhibiting factor from hypothalamus inhibits growth hormone secretion. 4. G H R H exerts a negative feedback on hypothalamus. 5. Growth hormone and somatomedins exert a positive feedback on hypothalamus. 6. Somatomedins also impose a negative feedback on anterior pituitary.
Fig. 9.11
Regulation of growth hormone secretion.
GHRH, Growth hormone–releasing hormone; IGF, insulin-like growth factor; SRIF, somatotropin release–inhibiting factor.
Growth hormone secretion is regulated by negative feedback (see Fig. 9.11 ). Three feedback loops including both long and short loops are involved. (1) GHRH inhibits its own secretion from the hypothalamus via an ultrashort-loop feedback. (2) Somatomedins, which are byproducts of the growth hormone action on target tissues, inhibit secretion of growth hormone by the anterior pituitary. (3) Both growth hormone and somatomedins stimulate the secretion of somatostatin by the hypothalamus. The overall effect of this third loop is inhibitory (i.e., negative feedback) because somatostatin inhibits growth hormone secretion by the anterior pituitary.
Tourism is a major contributor to global and national economies, creating jobs, supporting local businesses, and promoting cultural exchange. Yet, unchecked tourism often leads to environmental pollution, overuse of natural resources, and erosion of cultural heritage. Popular destinations such as hill stations, beaches, and heritage sites frequently suffer from over-crowding, waste mismanagement, and ecological imbalance. To address these issues, the idea of sustainable tourism has gained importance. It refers to tourism practices that meet the needs of present travelers without compromising the ability of future generations to enjoy the same destinations. By focusing on eco-friendly travel, preservation of biodiversity, and respect for cultural traditions, sustainable tourism seeks to strike a balance between economic benefits and environmental protection.
The success of sustainable tourism depends on collective efforts by governments, local communities, businesses, and tourists themselves. Governments must implement strict environmental regulations, limit tourist footfall in fragile ecosystems, and promote renewable energy-based infrastructure. Local communities should be empowered through community-based tourism, ensuring they earn income without losing their cultural identity. Businesses, such as hotels and travel agencies, can adopt green practices like waste recycling, energy conservation, and use of eco-friendly materials. Equally important is the role of travelers, who must adopt responsible habits such as reducing plastic use, respecting cultural norms, and supporting local artisans. Examples like eco-tourism projects in Kerala and Sikkim show how tourism can be made sustainable while still being profitable. In conclusion, sustainable tourism is not just about travel—it is about creating harmony between people, culture, and nature. Adopting it is essential for protecting our environment while ensuring tourism continues to fuel economic growth in the years ahead.
Tourism is a major contributor to global and national economies, creating jobs, supporting local businesses, and promoting cultural exchange. Yet, unchecked tourism often leads to environmental pollution, overuse of natural resources, and erosion of cultural heritage. Popular destinations such as hill stations, beaches, and heritage sites frequently suffer from over-crowding, waste mismanagement, and ecological imbalance. To address these issues, the idea of sustainable tourism has gained importance. It refers to tourism practices that meet the needs of present travelers without compromising the ability of future generations to enjoy the same destinations. By focusing on eco-friendly travel, preservation of biodiversity, and respect for cultural traditions, sustainable tourism seeks to strike a balance between economic benefits and environmental protection.
The success of sustainable tourism depends on collective efforts by governments, local communities, businesses, and tourists themselves. Governments must implement strict environmental regulations, limit tourist footfall in fragile ecosystems, and promote renewable energy-based infrastructure. Local communities should be empowered through community-based tourism, ensuring they earn income without losing their cultural identity. Businesses, such as hotels and travel agencies, can adopt green practices like waste recycling, energy conservation, and use of eco-friendly materials. Equally important is the role of travelers, who must adopt responsible habits such as reducing plastic use, respecting cultural norms, and supporting local artisans. Examples like eco-tourism projects in Kerala and Sikkim show how tourism can be made sustainable while still being profitable. In conclusion, sustainable tourism is not just about travel—it is about creating harmony between people, culture, and nature. Adopting it is essential for protecting our environment while ensuring tourism continues to fuel economic growth in the years ahead.
baba meitian kaiche qu shangban
huoche
shangban
xiaban
women meitian zoulu qu shangxue
gege xihuan qi zixingche
wo meitian zaoshang liudian zuo qiche qu xuexiao
ditie
muchuan
ni meitian zenme qu xuexiao
I told her how we had just last week recognized this very person for what he had done, for output, naturally, but also be-cause of its excellence. We know this person has that "magic touch."
I told her how we had just last week recognized this very person for what he had done, for output, naturally, but also be-cause of its excellence. We know this person has that "magic touch."
I spoke with one company visitor recently and she was very much impressed, she said, with the large amount of work she had noted being finished by one of our front office workers.
1.The group will meet at the Lakeview Hotel in Seattle, Washington.
2.The manager of the customer service department is Phillip Redfin.
3.Robin is enrolled in Accounting 101; Lee is in Marketing class.
4.Jan earned a Bachelor of Science Degree at Central State College.
5.Vice President Smith will speak at the sales meeting on Thursday.
6.Ginger Marks, PhD., is working to earn her CPA rating this year.
7.George is the leading sales representative in the western region.
8.We told them Smart Write is a registered trademark of Holt, Inc.
9.We will meet with the Governor in the northern part of the state.
10.I like the quote on page 43 of the new book on display in Room C.
11.If it rains this afternoon, Brenda will not play tennis with James.
12.The advertising department got a fifteen % increase in the budget.
13.Why did the company move their office to 1829 Westside Boulevard?
14.My manager, Douglas C. Westerfield got his MBA from Western College.
15.We plan to leave at 2:20 p.m. to go to a 3p.m. meeting.
16.Do you know with whom he plans to go to the game with on Friday night?
17.The typing prize is $10,000.00 cash and a $21,000.00 car.
18.The meeting is scheduled for March 8 at 5 o’clock in Building D.
19.Judy and Thomas are going to the mall after they finish their works.
20.Is the game schedule for Friday, March 6 or for Saturday, March 7?
21.Beach music was popular in the 60s but it was not as popular now.
22.The meeting was postponed by the secretary because the speaker is ill.
23.Jimmy drove passed his new house in the driving rain last night.
24.Jo Sanchez, head of the Finance Department called me at 8:30 a.m.
25.Did a sales representative sell Jennifer’s car for its full value?
26.The highway is very slippery, therefore, please drive very cautious.
27.A leader must encourage his employees to assume responsibilities.
28.Majorie should of course be invited to participate in the meeting.
29.They saw 48 ducks, 8 deer, 6 geese, 9 cows, 4 horses and 12 squirrels.
30.Elizabeth, the best tennis player on the team, injures her ankle today.
I spoke with one company visitor recently; and she was very much impressed, she said, with the large amount of work she had noted being finished by one of our front office workers.
I told her how we had just last week recognized this very person for what he had done, for output, naturally, but also be-cause of its excellence. We know this person has that "magic touch."
This "magic touch" is the ability to do a fair amount of work in a fair amount of time. It involves a desire to become ever more efficient without losing quality--the "touch" al workers should have.
Writing 9: 36, 38, 40 gwam
I spoke with one company visitor recovery, and she was very much impressed, she said, with the large amount of work she had noted being finished by one of our front office workers.
I told her how we had just last week recognized this very person for what he had done, for output, naturally, but also be-cause of its excellence. We know this person has that "magic touch."
This "magic touch" is the ability to do a fair amount of work in a fair amount of time. It involves a desire to become ever more efficient without losing quality--the "touch" al workers should have.
