Adenylate cyclase vasopressin-stimulated

This transmembrane signaling system involves a complex consisting of several functional proteins (Figure 7) stimulatory (e.g. P-adrenergic, dopamine Dp serotonin, vasopressin) [124] and inhibitory (e.g. a2-adrenergic, dopamine D2, opiod, and muscarinic) [125] receptors, stimulatory (Gs) and inhibitory (G ) G-proteins, and the catalytic protein, adenylate cyclase. On stimulation of a receptor, an associated G-protein binds GTP and the resulting receptor/G-protein/GTP complex then activates, or inhibits, adenylate cyclase in the catalysis of the synthesis... 

Li+ also inhibits several hormone-stimulated adenylate cyclases which, in some cases, appear to be related to side effects of Li+ therapy. For instance, Li+ inhibits the hydro-osmotic action of vasopressin, the antidiuretic hormone which increases water resorption in the kidney [136]. This effect is associated with polyuria, a relatively harmless side effect sometimes experienced with Li+ treatment, which arises from the inability of the kidney to concentrate urine. Li+ has been shown to inhibit vasopressin-stimulated adenylate cyclase activity in renal epithelial cells. Additionally, Li+ is reported to enhance the vasopressin-induced synthesis of prostaglandin E2 (PGE2) in vitro in kidney. PGE2 inhibits adenylate cyclase activity by stimulation of Gj, and, therefore, this effect may contribute to the Li+-induced polyuria. 

CRF. Activation of protein kinase C by phorbol esters or synthetic diacylglycerols of CRF-stimulated cells mimics the synergistic action of vasopressin and CRF [48]. As mentioned above, this may be mediated by phosphorylation by protein kinase C of one of the regulatory components of CRF-stimulated adenylate cyclase [48]. 

Fig. 8. Known and potential interactions of the ACTH/adenylate cyclase/cyclic AMP-dependent protein kinase system in the adrenocortical cell with other hormones and intracellular messengers. Epinephrine activates adenylate cyclase in the adrenocortical cell [33]. Adrenocortical cells have receptors for several hormones which may activate G, including angiotensin II [34], acetylcholine [35], and endogenous opioid peptides [36]. Angiotensin II, acetylcholine and vasopressin [37-39] have all been demonstrated to activate the breakdown of PIP2 in adrenocortical cells and to stimulate steroidogenesis 5-hydroxytrypt-amine is also a known steroidogenic agent [40]. Probable receptor subtypes involved are indicated (/3 M (muscarinic) 5-HT, and V,). This is not a comprehensive diagramming of all stimuli or all possible interactions. Modified from Ref. 7.

Methylxanthines inhibit phosphodiesterase in many tissues, and theophylline is about six times as potent as caffeine [6]. The potentiation of drug effects by methylxanthines has often been interpreted as accumulation of cyclic AMP, but methylxanthines also promote the accumulation of cyclic GMP [37]. Methylxanthines also inhibit adenylate cyclase activity in some tissues, as, for example, the noradrenaline-stimulated adenylate cyclase activity in rat erythrocyte ghosts [38], the vasopressin-stimulated adenylate cyclase activity in toad bladder epithelium [39], the increase in cyclic AMP produced in brain slices by depolarising stimuli and by adenosine [40], and the adenylate cyclase activity in guinea-pig lung particles [41]. Both basal and glucagon-stimulated phosphorylase activity in rat liver slices are inhibited by theophylline [42]. However, methylxanthines also have pharmacological effects which are not related to inhibition of phosphodiesterase [43]. 

Response of the adenylate cyclase system to a hormone is determined by the types and amounts of various constituent proteins. Cyclic AMP production is limited by the amount of adenylate cyclase present. When all the adenylate cyclase is fully stimulated, further hormone binding to Rs s cannot increase the rate of cAMP synthesis. In cells having many different Rs s (adipocytes have them for epinephrine, ACTH, TSH, glucagon, MSH, and vasopressin), maximal occupancy of the receptors may not... 

Cortisol secretion by isolated adrenal pouches in hypoxed dogs was stimulated by cyclic AMP, vasopressin and ACTH O. However, epinephrine and norepinephrine, which stimulate formation of cyclic AMP in fat pads, dichloroisoproterenol, which inhibits adenyl cyclase, or dihydroergota-mine, an inhibitor of action of cyclic AMP in the liver, failed to have any effect. 

It has been suggested that these diuretic and natriuretic effects result from an inhibition of the action of vasopressin, an effect which has been observed in the isolated toad bladder and rabbit renal tubule, where PGEi inhibits vasopressin-induced water permeability [12, 13, 417-419]. It is postulated that vasopressin activates adenyl cyclase, thus increasing cyclic AMP formation, which in turn leads to an increase in water permeability. PGEj may then inhibit the vasopressin and hence reduce the permeability by acting via the adenyl cyclase in the same way as it reduces hormone-stimulated lipiolysis [13,404,407, 410,412]. 

PGE can stimulate or inhibit its own hormone-induced synthesis via an ability to stimulate cAMP production. In the canine renal collecting tubule there appear to be two PGE receptors ". One of these receptors is an inhibitory receptor which modulates vasopressin-induced H2O flow . The other receptor is coupled to stimulation of adenylate cyclase activity. This latter receptor may be involved in inhibition of arachidonate release and feedback inhibition of hormone-induced PGE production. Similarly, neutrophil activation (and PGE2 synthesis) induced by f-met-leu-phe is under feedback inhibitory control by a PGE receptor apparently coupled to The opposite situation occurs in the thyroid. In the thyroid, there are two phases to PGE synthesis. The second phase is cAMP dependent and PGE serves to augment its own synthesis by its ability to stimulate adenylate cyclase activity ... 

Mechanisms of Renal Water Reabsorption - Much experimental evidence supports the hypothesis, first advanced by Orloff and Handler, that sodium transport and osmotic water flow that characterizes the physiological response to vasopressin.In a recent study. Chase and Aurbach have Identified two distinct adenyl cyclase systems located In renal membrane fractions of rats, one In the cortex and the other In the medulla.While the medullary enzyme was stimulated by vasopressin, cortex adenyl cyclase was more responsive to parathyroid hormone than vasopressin. The localization of parathyroid-sensitive adenyl cyclcise In renal cortex and vasopressin-sensitive adenyl cyclase in renal medulla appears to be consistent with reports that cellular transfer of calcium and phosphate occurs primarily in the proximal portions of the nephron, and sodium transport and water permeability are stimulated by vasopressin mainly In the collecting tubules. Vasopressin-Induced stimulation of adenyl cyclase In the cortex may reflect Its additional action on the distal tubule. 

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