Color Atlas of Physiology 2003 thieme

stimuli (!p. 170), whereas the release of melatonin is subject to afferent neuron control (!p. 334).

Some of these hormones (e.g., angiotensin II) and tissue hormones or mediators exert paracrine effects within endocrine and exocrine glands, the stomach wall, other organs, and on inflammatory processes. Bradykinin (!pp. 214 and 236), histamine (!pp. 100 and 242), serotonin (5-hydroxytryptamine, !p. 102) and eicosanoids are members of this group.

Eicosanoids. Prostaglandins (PG), thromboxane (TX), leukotrienes and epoxyeicosatrienoates are eicosanoids (Greek ει!%σι = twenty [C atoms]) derived in humans from the fatty acid arachidonic acid (AA). (Prostaglandins derived from AA have the index number 2). AA occurs as an ester in the phospholipid layer of the cell membranes and is obtained from dietary sources (meat), synthesized from linoleic acid, an essential fatty acid, and released by phospholipase A2 (!p. 252).

Pathways of eicosanoid synthesis from arachidonic acid (AA):

1.Cyclooxygenase pathway: Cyclooxygenase (COX)-1

and COX-2 convert AA into PGG2, which gives rise to PGH2, the primary substance of the biologically active compounds PGE2, PGD2, PGF2α, PGI2 (prostacyclin) and TXA2. COX-1 and 2 are inhibited by nonsteroidal anti-inflammatory drugs (e.g., Aspirin!).

2.Lipoxygenase pathway: Leukotriene A4 is synthesized from AA (via the intermediate 5-HPETE = 5-hy- droperoxyeicosatetraenoate) by way of 5-lipoxy- genase (especially in neutrophilic granulocytes).

Leukotriene A4 is the parent substance of the leukotrienes C4, D4 and E4. The significance of 12lipoxygenase (especially in thrombocytes) is not yet clear, but 15-lipoxygenase is known to produce vasoactive lipoxins (LXA4, LXB4).

3.Cytochrome P450-epoxygenase produces epoxyeicosatrienoates (EpETrE = EE).

Typical effects of eicosanoids:

PGE2 dilates the bronchial and vascular musculature (and keeps the lumen of the fetal ductus arteriosus and foramen ovale open; !p. 220), stimulates intestinal and uterine contractions, protects the gastric mucosa (!p. 242), inhibits lipolysis, increases the glomerular filtration rate (GFR), plays a role in fever development (!p. 224), sensitizes nociceptive nerve endings (pain) and increases the

permeability of blood vessels (inflammation). PGD2 induces bronchoconstriction. PGI2 (prostacyclin) synthesized in the endothelium, is vasodilatory and inhibits platelet aggregation. TXA2, on the other hand, occurs in platelets, promotes platelet aggregation and acts as a vasoconstrictor (!p. 102). 11,12-EpETrE has a vasodilatory effect (= EDHF, !p. 214).

Hormones (h.) of the hypothalamus and pituitary

Name* Abbreviation/synonyme

Hypothalamus

The suffix “-liberin” denotes releasing

h. (RH) or factor (RF); “-statin” is used for releaseinhibiting h. (IH) or factors (IF)

** Names generally recommended by IUPAC-IUB Committee on Biochemical Nomenclature.

** Also synthesized in gastrointestinal organs, etc.

269

Testosterone

Estrogens

Gestagens (progesterone)

Thyroxin (T4)

Deiodinization

Triiodothyronine (T3)

Somatomedins (IGF)

Angiotensin II

Mineralocorticoids

Per-

Glucocorticoids mis- sive

Androgens

Plate 11.2 u. 11.3 Hormones

271

11 Hormones and Reproduction

272

Humoral Signals: Control and Effects

Hormones and other humoral signals function to provide feedback control, a mechanism in which the response to a signal feeds back on the signal generator (e.g., endocrine gland). The speed at which control measures are implemented depends on the rate at which the signal substance is broken down—the quicker the degradation process, the faster and more flexible the control.

In negative feedback control, the response to a feedback signal opposes the original signal. In the example shown in A1, a rise in plasma cortisol in response to the release of corticoliberin (corticotropin-releasing hormone, CRH) from the hypothalamus leads to down-regulation of the signal cascade “CRH ! ACTH ! adrenal cortex,” resulting in a decrease in cortisol secretion. In shorter feedback loops, ACTH can also negatively feed back on the hypothalamus ( !A2), and cortisol, the end-hormone, can negatively feed back on the anterior pituitary (!A3). In some cases, the metabolic parameter regulated by a hormone (e.g., plasma glucose concentration) rather then the hormone itself represents the feedback signal. In the example (!B), glucagon increases blood glucose levels (while insulin decreases them), which in turn inhibits the secretion of glucagon (and stimulates that of insulin). Neuronal signals can also serve as feedback (neuroendocrine feedback) used, for example, to regulate plasma osmolality (!p. 170).

In positive feedback control, the response to the feedback amplifies the original signal and heightens the overall response (e.g., in autocrine regulation; see below).

The higher hormone not only controls the synthesis and excretion of the end-hormone, but also controls the growth of peripheral endocrine gland. If, for example, the end-hor- mone concentration in the blood is too low despite maximum synthesis and secretion of the existing endocrine cells, the gland will enlarge to increase end-hormone production. This type of compensatory hypertrophy is observed for instance in goiter development (!p. 288) and can also occur after surgical excision of part of the gland.

Therapeutic administration of a hormone (e.g., cortisone, a cortisol substitute) have the same effect on higher hormone secretion (ACTH and CRH in the example) as that of the end-hormone (cortisol in the example) normally secreted by the peripheral gland (adrenal cortex in this case). Long-term administration of an end-hormone would therefore lead to inhibition and atrophy of the endocrine gland or cells that normally produce that hormone. This is known as compensatory atrophy.

A rebound effect can occur if secretion of the higher hormone (e.g., ACTH) is temporarily elevated after discontinuation of end-hor- mone administration.

The principal functions of endocrine hormones, paracrine hormones and other humoral transmitter substances are to control and regulate:

enzyme activity by altering the conformation (allosterism) or inhibiting/stimulating the synthesis of the enzyme (induction);

transport processes, e.g., by changing the rate of insertion and synthesis of ion channels/ carriers or by changing their opening probability or affinity;

growth (see above), i.e., increasing the rate of mitosis (proliferation), “programmed cell death” (apoptosis) or through cell differentiation or dedifferentiation;

secretion of other hormones. Regulation can occur via endocrine pathways (e.g., ACTH-me- diated cortisol secretion; !A5), a short portal vein-like circuit within the organ (e.g., effect of CRH on ACTH secretion, !A4), or the effect of cortisol from the adrenal cortex on the synthesis of epinephrine in the adrenal medulla, (!A6), or via paracrine pathways (e.g., the effect of somatostatin, SIH, on the secretion of insulin and glucagon; !B).

Cells that have receptors for their own humoral signals transmit autocrine signals that function to

exert negative feedback control on a target cell, e.g., to discontinue secretion of a transmitter (e.g., norepinephrine; !p. 84);

coordinate cells of the same type (e.g., in growth);

exert positive feedback control on the secreting cell or to cells of the same type. These mechanisms serve to amplify weak signals as is observed in the eicosanoid secretion or in T cell clonal expansion (!p. 96ff.).

Cellular Transmission of Signals from Extracellular Messengers

GTP (cytosolic cAMP concentration rises) and inhibited by αi-GTP (cAMP concentration falls;

!A3).

Gs-activating messengers. ACTH, adenosine (A2A and A2B rec.), antidiuretic hormone = vasopressin (V2 rec.), epinephrine and norepinephrine ("1, "2, "3 adrenoceptors), calcitonin, CGRP, CRH, dopamine (D1 and D5 rec.), FSH, glucagon, histamine (H2 rec.), oxytocin (V2 rec., see above), many prostaglandins (DP, IP, EP2 and EP4 rec.), serotonin = 5-hydroxytrypt- amine (5-HT4 and 5-HT7 rec), secretin and VIP activate Gs proteins, thereby raising cAMP levels. TRH and TSH induce partial activation.

Gi-activating messengers. Some of the above messenger substances also activate Gi proteins (thereby lowering cAMP levels) using a different binding receptor. Acetylcholine (M2 and M4 rec.), adenosine (Al and A3 rec.), epinephrine and norepinephrine (α2 adrenoceptors), angiotensin II, chemokines, dopamine (D2, D3 and D4 rec.), GABA (GABAB rec.), glutamate (mGLU2–4 and mGLU6–8 rec.), melatonin, neuropeptide Y, opioids, serotonin = 5-hydroxytryptamine (5-HTl rec.), somatostatin and various other substances activate Gi proteins.

Effects of cAMP. cAMP activates type A protein kinases (PKA = protein kinase A) which then activate other proteins (usually enzymes and membrane proteins, but sometimes the receptor itself) by phosphorylation (!A4). The specific response of the cell depends on the type of protein phosphorylated, which is determined by the type of protein kinases present in the target cell. Phosphorylation converts the proteins from an inactive to an active form or vice versa.

Hepatic glycogenolysis, for instance, is dually increased by cAMP and PKA. Glycogen synthase catalyzing glycogen synthesis is inactivated by phosphorylation whereas glycogen phosphorylase stimulating glycogenolysis is activated by cAMP-mediated phosphorylation.

Signal transduction comprises the entire signaling pathway from the time the first messenger binds to the cell to the occurrence of cellular effect, during which time the signal can be (a) modified by other signals and

(b) amplified by many powers of ten. A single adenylate cyclase molecule can produce numerous cAMP and PKA molecules, which in turn can phosphorylate an enormous number of enzyme molecules. The interposition of more kinases can lead to the formation of long