Файл: BRS_Physiology_6E_2014_1.pdf

Physiologic

actions

Figure 7.2 Mechanism of hormone action—inositol 1,4,5-triphosphate (IP3)–Ca2+. GDP = guanosine diphosphate; GTP = guanosine triphosphate; PIP2 = phosphatidylinositol 4,5-diphosphate.

1.  Guanylyl cyclase

a.  Atrial natriuretic peptide (ANP) acts through receptor guanylyl cyclase, where the extracellular side of the receptor binds ANP and the intracellular side of the receptor has guanylyl cyclase activity. Activation of guanylyl cyclase converts GTP to cyclic GMP, which is the second messenger.

b.  Nitric oxide (NO) acts through cytosolic guanylyl cyclase. Activation of guanylyl cyclase converts GTP to cyclic GMP, which is the second messenger.

2.  Tyrosine kinases (Figure 7.3)

■Hormone binds to extracellular receptors that have, or are associated with, tyrosine kinase activity. When activated, tyrosine kinase phosphorylates tyrosine moieties on proteins, leading to the hormone’s physiologic actions.

a.  Receptor tyrosine kinase

■Hormone binds to the extracellular side of the receptor.

■The intracellular side of the receptor has intrinsic tyrosine kinase activity.

■One type of receptor tyrosine kinase is a monomer (e.g., receptor for nerve growth factor). Binding of hormone or ligand causes dimerization of the receptor, activation of intrinsic tyrosine kinase, and phosphorylation of tyrosine moieties.

■Another type of receptor tyrosine kinase is a dimer (e.g., receptors for insulin and insulin-like growth factor (IGF). Binding of hormone activates intrinsic tyrosine kinase, leading to phosphorylation of tyrosine moieties.

■Insulin receptors are also discussed in Section VI C 2.

b.  Tyrosine kinase–associated receptor

■is the mechanism of action of growth hormone.

■Growth hormone binds to the extracellular side of the receptor.

■The intracellular side of the receptor does not have tyrosine kinase activity but is non-

covalently associated with tyrosine kinase (e.g., Janus family of receptor-­associated tyrosine kinase, JAK).

Tyrosine kinase– associated receptors

Growth hormones

Growth hormone receptor

fIGUre 7.3 Tyrosine kinase receptors. Nerve growth factor and insulin utilize receptor tyrosine kinases. Growth hormone utilizes a tyrosine kinase–associated receptor. JAK = Janus family of receptor-associated tyrosine kinase; NGF = nerve growth factor.

■Binding of growth hormone causes dimerization of the receptor and activation of tyrosine kinase in the associated protein (e.g., JAK).

■Targets of JAK include signal transducers and activators of transcription (sTAT), which cause transcription of new mRNAs and new protein synthesis.

e.steroid hormone and thyroid hormone mechanism (figure 7.4)

1.Steroid (or thyroid) hormone diffuses across the cell membrane and binds to its receptor (step 1).

2.The hormone–receptor complex enters the nucleus and dimerizes (step 2).

3.The hormone–receptor dimers are transcription factors that bind to steroid-responsive elements (sres) of DNA (step 3) and initiate DNA transcription (step 4).

4.new messenger rnA is produced, leaves the nucleus, and is translated to synthesize new proteins (step 5).

5.The new proteins that are synthesized have specific physiologic actions. For example, 1,25-dihydroxycholecalciferol induces the synthesis of calbindin D-28K, a Ca2+-binding protein in the intestine; aldosterone induces the synthesis of Na+ channels in the renal principal cells.

POMC

Figure 7.5 Proopiomelanocortin (POMC) is the precursor for adrenocorticotropic hormone (ACTH), β-lipotropin, and β-endorphin in the anterior pituitary.

1.  TSH, LH, and FSH

■belong to the same glycoprotein family. Each has an α subunit and a β subunit. The a subunits are identical. The β subunits are different and are responsible for the unique biologic activity of each hormone.

2.  ACTH, melanocyte-stimulating hormone (MSH), b-lipotropin, and b-endorphin (Figure 7.5)

■are derived from a single precursor, proopiomelanocortin (POMC).

■a-MSH and b-MSH are produced in the intermediary lobe, which is rudimentary in adult humans.

3.  Growth hormone (somatotropin)

■is the most important hormone for normal growth to adult size.

■is a single-chain polypeptide that is homologous with prolactin and human placental lactogen.

a.  Regulation of growth hormone secretion (Figure 7.6)

■Growth hormone is released in pulsatile fashion.

■Secretion is increased by sleep, stress, hormones related to puberty, starvation, exercise, and hypoglycemia.

■Secretion is decreased by somatostatin, somatomedins, obesity, hyperglycemia, and pregnancy.

(1)  Hypothalamic control—GHRH and somatostatin

■GHRH stimulates the synthesis and secretion of growth hormone.

■Somatostatin inhibits secretion of growth hormone by blocking the response of the anterior pituitary to GHRH.

(2)  Negative feedback control by somatomedins

■Somatomedins are produced when growth hormone acts on target tissues. Somatomedins inhibit the secretion of growth hormone by acting directly on the anterior pituitary and by stimulating the secretion of somatostatin from the hypothalamus.

(3)  Negative feedback control by GHRH and growth hormone

■GHRH inhibits its own secretion from the hypothalamus.

■Growth hormone also inhibits its own secretion by stimulating the secretion of somatostatin from the hypothalamus.