книги студ / color atlas of physiology 5th ed[1]. (a. despopoulos et al, thieme 2003)

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Enzyme-Linked Cell Surface Receptors For Messenger Substances

3. Receptor serine/threonine kinases, which like the TGF-! receptor, function similar to kinases in Group 2, the only difference being that they phosphorylate serine or threonine residues of the target protein instead of tyrosine residues (as with PKC; see above).

4.Tyrosine kinase-associated receptors are those where the receptor works in combination with non-receptor tyrosine kinases (chiefly proteins of the Src family) that phosphorylate the target protein. The receptors for STH, prolactin, erythropoietin and numerous cytokines belong to this group.

5.Receptor tyrosine phosphatases remove phosphate groups from tyrosine residues. The CD45 receptor involved in T cell activation belongs to this group.

Hormones with Intracellular Receptors

Steroid hormones (!p. 270ff., yellow areas), 278 calcitriol and thyroid hormones are like other

hormones in that they induce a specific cell response with the difference being that they activate a different type of signaling cascade in the cell. They are lipid-soluble substances that freely penetrate the cell membrane.

Steroid hormones bind to their respective cytoplasmic receptor protein in the target cell (!D). This binding leads to the dissociation of inhibitory proteins (e.g., heat shock protein, HSP) from the receptors. The hormone–recep- tor protein complex (H–R complex) then migrates to the cell nucleus (translocation), where it activates (induces) or inhibits the transcription of certain genes. The resulting increase or decrease in synthesis of the respective protein (e.g., AIPs; !p. 182) is responsible for the actual cell response (!D).

Triiodothyronine (T3; !p. 286ff.) and calcitriol (!p. 292) bind to their respective receptor proteins in the cell nucleus (nuclear receptors). These receptors are hormone-acti- vated transcription factors. Those of calcitriol can induce the transcription of calcium-bind- ing protein, which plays an important role in interstitial Ca2+ absorption (!p. 262).

Recent research indicates that steroid hormones and calcitriol also regulate cell function by non-genomic control mechanisms.

Nitric Oxide as a Transmitter Substance

In nitrogenergic neurons and endothelial tissues, nitric (mon)oxide (NO) is released by Ca2+/calmodulin-mediated activation of neuronal or endothelial nitric oxide synthase (NOS) (!E). Although NO has a half-life of only a few seconds, it diffuses into neighboring cells (e.g., from endothelium to vascular myocytes) so quickly that it activates cytoplasmic guanylyl cyclase, which converts GTP into cGMP (!E). Acting as a second messenger, cGMP activates protein kinase G (PKG), which in turn decreases the cytosolic Ca2+ concentration [Ca2+]i by still unexplained mechanisms. This ultimately leads to vasodilatation (e.g., in coronary arteries).

Penile erections are produced by cGMP-mediated vasodilatation of the deep arteries of the penis (!p. 308). The erection can be prolonged by drugs that inhibit cGMP-specific phosphodiesterase type 5, thereby delaying the degradation of cGMP (e.g., sildenafil citrate = Viagra!).

Hypothalamic–Pituitary System

In the hypothalamus, (1) humoral signals from the periphery (e.g., from circulating cortisol) can be converted to efferent neuronal signals, and (2) afferent neuronal signals can be converted to endocrine messengers (neurosecretion).

Oxytocin (Ocytocin) and antidiuretic hormone (ADH) are two posterior pituitary hormones that enter the systemic circulation directly. ADH induces water retention in the renal collecting ducts (V2-rec.; !p. 166) and induces vasoconstriction (endothelial V1 rec.) by stimulating the secretion of endothelin-1 (!p. 212ff.). ADH-bearing neurons also secrete ADH into the portal venous circulation (see below). The ADH and CRH molecules regulate the secretion of ACTH by the adenohy-

280pophysis. Oxytocin promotes uterine contractions and milk ejection (!p. 304). In nursing

mothers, suckling stimulates nerve endings in the nipples, triggering the secretion of oxytocin (and prolactin, !p. 303) via neurohumoral reflexes.

Releasing hormones (RH) or liberins that stimulate hormone release from the adenohypophysis (Gn-RH, TRH, SRH, CRH; !p. 270ff.) are secreted by hypothalamic neurons into a kind of portal venous system and travel only a short distance to the anterior lobe (!A). Once in its vascular network, they trigger the release of anterior pituitary hormones into the systemic circulation (!A). Some anterior pituitary hormones are regulated by release-inhib- iting hormones (IH) or statins, such as SIH and PIH = dopamine (!p. 270ff.). Peripheral hormones, ADH (see above) and various neurotransmitters such as neuropeptide Y (NPY), norepinephrine (NE), dopamine, VIP and opioids also help to regulate anterior pituitary functions (!p. 272).

The four glandotropic hormones (ACTH, TSH, FSH and LH) and the aglandotropic hormones (prolactin and GH) are secreted from the anterior pituitary (!A). The secretion of growth hormone (GH = somatotropic hormone, STH) is subject to control by GH-RH, SIH and IGF-1. GH stimulates protein synthesis (anabolic action) and skeletal growth with the aid of somatomedins (growth factors formed in the liver), which play a role in sulfate uptake by cartilage. Somatomedin C = insulin-like growth factor-1 (IGF-1) inhibits the release of GH by the anterior pituitary via negative feedback control. GH has lipolytic and glycogenolytic actions that are independent of somatomedin activity.

Proopiomelanocortin (POMC) is a peptide precursor not only of ACTH, but (inside or outside the anterior pituitary) also of !-endorphin and α-melano- cyte-stimulating hormone (α-MSH = α-melanocor- tin). !-endorphin has analgesic effects in the CNS and immunomodulatory effects, while α-MSH in the hypothalamus helps to regulate the body weight (!p. 230) and stimulates peripheral melanocytes.

A. Hypothalamic-pituitary hormone secretion (schematic)

Superior hypophysial artery

Axoplasmic transport by neurosecretory nerve cells

Release of RHs, IHs, ADH, NE, NPY and

other transmitters

anterior pituitary hormones

IH inhibit their release

Plate 11.8 Hypothalamic–Pituitary System

281

Plate 11.9 Carbohydrate Metabolism I

283

284stimulated by AA from digested proteins (especially alanine and arginine) as well as by hy-

poglycemia (e.g., due to fasting, prolonged physical exercise; !B) and sympathetic impulses (via !2 adrenoceptors; !A). Glucagon secretion is inhibited by glucose and SIH (!p. 273, B) as well as by high plasma concentrations of free fatty acids.

The actions of glucagon (!A, B, C) (via cAMP; !p. 274) mainly antagonize those of insulin. Glucagon maintains a normal blood glucose level between meals and during phases of increased glucose consumption to ensure a constant energy supply. It does this (a) by increasing glycogenolysis (in liver not muscle) and (b) by stimulating gluconeogenesis from lactate, AA (protein degradation = catabolism) and glycerol (from lipolysis).

Increased plasma concentrations of amino acids (AA) stimulate insulin secretion which would lead to hypoglycemia without the simultaneous ingestion of glucose. Hypoglycemia normally does not occur, however, since AA also stimulate the release of glucagon, which increases the blood glucose concentration. Glucagon also stimulates gluconeogenesis from AA, so some of the AA are used for energy production. In order to increase protein levels in patients, glucose must therefore be administered simultaneously with therapeutic doses of AA to prevent their metabolic degradation.

Somatostatin (SIH). Like insulin, SIH stored in D cells (SIH 14 has 14 AA) is released in response to increased plasma concentrations of glucose and arginine (i.e., after a meal). Through paracrine pathways (via Gi-linked receptors), SIH inhibits the release of insulin (!p. 273, B). Therefore, SIH inhibits not only the release of gastrin, which promotes digestion (!p. 243, B3), but also interrupts the in- sulin-related storage of nutrients. SIH also inhibits glucagon secretion (!p. 273 B). This effect does not occur in the presence of a glucose deficiency because of the release of catecholamines that decrease SIH secretion.

Somatotropin (STH) = growth hormone (GH). The short-term effects of GH are similar to those of insulin; its action is mediated by somatomedins (!p. 280). In the long-term, GH increases the blood glucose concentration and promotes growth.

The effects of glucocorticoids on carbohydrate metabolism are illustrated on plate C and explained on p. 296.

B. Hormone synthesis and secretion

3 Hormone secretion

Plate 11.11 Thyroid Hormones I

287