Adenylate cyclase activators

Two AT-II receptors, AT and AT2 are known and show wide distribution (27). The AT receptor has been cloned and predominates ia regions iavolved ia the regulation of blood pressure and water and sodium retention, eg, the aorta, Hver, adrenal cortex, and ia the CNS ia the paraventricular nucleus, area postrema, and nucleus of the soHtary tract. AT2 receptors are found primarily ia the adrenal medulla, utems, and ia the brain ia the locus coeruleus and the medial geniculate nucleus. AT receptors are GCPRs inhibiting adenylate cyclase activity and stimulating phosphoHpases C, A2, and D. AT2 receptors use phosphotyrosiae phosphatase as a transduction system. 

Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase Activating Peptide. Vasoactive intestinal peptide (VIP)... 

J (339), a 28-amino acid peptide, is a member of a family of stmctuially related peptides that includes secretin [1393-25-5] (340), growth hormone releasing factor (GRF), and pituitary adenylate cyclase-activating peptide (PACAP) [137061(341) (83). 

Forskolin (5-[acetyloxy]-3-ethenyldodecahydro-6,10,10b-trihydroxy-3,4a,7,7,10a-penta-methyl-[3R- 3a-4aP, SP, 6P, 6aa,10a, lOaP, 10ba -lFf-naphtho[2,l-b]pyran-l-one) [66575-29-9] M 410.5, m 229-232°, 228-233°. Recrystd from CfiH6-pet ether. It is antihypertensive, positive ionotropic, platelet aggregation inhibitory and adenylate cyclase activating properties [Chem AbstrS9 1978 244150, de Souza et al. Med Res Rev 3 201 1983]. 

Caffeine is also effective in the antagonism of peripheral adenosine (type I) receptors, which are known to inhibit lipolysis by subduing adenylate cyclase activity.28 The appeal of this mechanism of action is that the majority of the pharmacological effects of adenosine on the central nervous system can be inhibited by doses of caffeine that are well within physiologically non-toxic levels comparable to only a couple of cups of coffee.5... 

Ehlert FJ. Gallamine allosterically antagonizes muscarinic receptor-mediated inhibition of adenylate cyclase activity in the rat myocardium. J Pharmacol Exp Ther 1988 247 596-602. 

A G-protein-mediated effect has an absolute requirement for GTP. Reference has already been made to the requirement for GTP in reconstituting hormone-stimulated adenylate cyclase activity. A similar requirement can be demonstrated when the effector is an ion channel, such as the cardiac atrial inward-rectifier K+ channel which is activated following stimulation of the M2 muscarinic acetylcholine receptor. Thus, in the experiment illustrated in Figure 7.8, the channel recorded with a cell-... 

Dexamethasone (M S) l Adenylate cyclase activity Bovine cornea [20]... 

RJ Walkenbach, RD LeGrand. (1982). Inhibition of adenylate cyclase activity in the corneal epithelium by anti-inflammatory steroids. Exp Eye Res 34 161-168. 

Pataki et al. showed that apomorphine and bromocriptine enhanced the elevation of body temperature induced by pituitary adenylate cyclase-activating polypeptide in rats and observed that hyperthermia was antagonized by haloperidol, suggesting the involvement of the dopaminergic system (100). 

Pataki I, Adamik A, Jaszberenyi M, Macsai M, Telegdy G. Involvement of transmitters in pituitary adenylate cyclase-activating polypeptide-induced hyperthermia. 

Young, J.L. (1979) The effect of dimethyl 3,3 -dithiobispropionimidate on the adenylate cyclase activity of bovine corpus luteum. FEBS Lett. 104, 294-296. 

Calcitonin lowers serum Ca2+ and Pi levels, primarily by inhibiting the process of bone resorption, but also by decreasing resorption of Pi and Ca2+ in the kidney. Calcitonin receptors are predictably found primarily on bone cells (osteoclasts) and renal cells, and generation of cAMP via adenylate cyclase activation plays a prominent role in hormone signal transduction. 

Dopamine acts on G-protein-coupled receptors belonging to the D1 -family of receptors (so-called D1-like receptors , or DlLRs, comprised of Dl- and D5-receptors), and the D2-family of receptors ( D2-like receptors , or D2LRs comprised of D2-, D3- and D4-receptors). Dl LRs stimulate adenylate cyclase activity and, possibly, also phosphoinosit-ide hydrolysis, while D2LRs reduce adenylate cyclase activity. In the striatum, DlLRs are predominately associated with medium spiny neurons of the direct pathway, while D2LRs have been found as autoreceptors on dopaminergic terminals, as heteroreceptors on cholinergic interneurons, and on indirect pathway neurons. In the SNr, DlLRs are located on terminals of the direct pathway projection, while D2LRs appear to function as autoreceptors. 

The effects of Li+ upon this system have been reviewed in depth by Mork [131]. Animal studies originally demonstrated that Li+ inhibits cAMP formation catalyzed by adenylate cyclase in a dose-dependent manner [132]. The level of cAMP in the urine of manic-depressive patients changes with mental state, being abnormally elevated during the switch period between depression and mania it is proposed that Li+ s inhibitory effect upon adenylate cyclase activity may correct this abnormality. Subsequent research, in accord with the initial experiments, have shown that Li+ s interference with this second messenger system involves more than one inhibitory action. At therapeutic levels, Li+ inhibits cAMP accumulation induced by many neurotransmitters and hormones, both in... 

Li+, at therapeutically relevant concentrations, is a potent inhibitor of norepinephrine-stimulated adenylate cyclase activity ex vivo in both rat [133] and human brain [134], and it inhibits norepinephrine-stimulated cAMP accumulation in Li+-treated patients. Li+ also inhibits dopamine-stimulated cAMP accumulation in rat brain [135]. These inhibitory effects of Li+ have been shown to be region specific within rat brain, a fact that has obvious significance for a therapeutic mechanism of action. It is interesting that other antimanic drugs may also have dampening effects on dopaminergic neurotransmission. 

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. 

Mg2+ is competitive with the Li+ inhibition of both postreceptor G-protein stimulation [140], and direct stimulation of adenylate cyclase [141]. Li+ inhibits Mn2+-stimulated adenylate cyclase activity in membranes in the presence, but not in the absence, of calmodulin. Since, Mn2+ can replace Ca2+ in activating calmodulin, it is likely that the observed inhibition is that of the Mn2+-dependent calmodulin stimulation of the enzyme. In the absence of calmodulin, stimulation of adenylate cyclase is probably due to substitution of Mn2+ for Mg2+ in the substrate, MnATP2+ and this is unaffected by Li+. 

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