Adenylate cyclase activity inhibition

In Chinese hamster ovary cells transfected with the recombinant human TSH receptor, lemon balm produced a dose-dependent inhibition of TSH-stimulated adenylate cyclase activity, inhibited the cAMP production stimulated by TSH receptor antibody, and produced a significant inhibition of TSH binding to its receptor and of antibody binding to TSH (Santini et al. 2003). 

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. 

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. 

G, is the G-protein responsible for inhibiting adenylate cyclase. The inhibition is mediated by the a subunit. Unlike Gs, G, is not affected by CTx but instead is ADP-ribosylated (and inhibited) by PTx. Of the three isoforms of G, (Gn 3), an is the most potent inhibitor of cyclase. G, also activates inward-rectifier (Kir3.1/3.2 and Kir 3.1/3.4) K+ channels (GIRK channels), and this activation is mediated by released f v subunits (see below). 

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

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. 

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+. 

Figure 6.1. Regulation of adenylate cyclase activity by G-proteins. Occupancy of receptors such as the /3-adrenergic receptor result in the activation (+) of adenylate cyclase via coupling through stimulatory G-proteins (Gs). Alternatively, occupancy of receptors such as the 2-adrenergic receptor inhibit (-) adenylate cyclase via coupling through inhibitory G-proteins (Gj).

Dopamine-sensitive adenylate cyclase activity was early demonstrated in both the retina and the cervical ganglion of the cow [47] and later in homogenates of the caudate-putamen of the rat brain [48]. Kebabian has recently reviewed the biochemical components of dopamine-sensitive adenylate cyclase and the physiological role of the D1 receptor [49]. D1 and D2 agonists stimulate and inhibit adenylate cyclase activity, respectively. 

ADP ribosylation results in inhibition of GTPase activity and hence maintains the a-subunit in the active form. The constant activity of the G-protein results in an increase in adenyl cyclase activity and therefore a chronic increase in the cychc AMP level. This stimulates an ion channel in the enterocyte which results in a loss of Na ions and hence water from the cells into the intestine. This leads to diarrhoea and a massive loss of fluid from the body which can be sufficiently severe to result in death. Since 2000 there have been epidemics in South America and parts of central Africa. Infection is usually caused by drinking water contaminated with faecal matter. Treatment consists of hydration with rehydration fluids (Chapter 5). 

Stimulation of the parasympathetic system releases acetylcholine at the neuromuscular junction in the sinoatrial node. The binding of acetylcholine to its receptor inhibits adenylate cyclase activity and hence decreases the cyclic AMP level. This reduces the heart rate and hence reduces cardiac output. This explains why jumping into very cold water can sometimes stop the heart for a short period of time intense stimulation of the vagus nerve (a parasympathetic nerve) markedly increases the level of... 

Many monoamine neurotransmitters are now thought to work by this receptor-linked second messenger system. In some cases, however, stimulation of the posts)maptic receptors can cause the inhibition of adenylate cyclase activity. For example, D2 dopamine receptors inhibit, while receptors stimulate, the activity of the cyclase. 

Two types of dopamine receptors have been characterized in the mammalian brain, termed and D2. This subtyping largely arose in response to the finding that while all types of clinically useful neuroleptics inhibit dopaminergic transmission in the brain, there is a poor correlation between reduction in adenylate cyclase activity, believed to be the second messenger linked to dopamine receptors, and the clinical potency of the drugs. This was particularly true for the butyrophenone series (e.g. haloperidol) which are known to be potent neuroleptics and yet are relatively poor at inhibiting adenylate cyclase. 

Many of the adverse effects of lithium can be ascribed to the action of lithium on adenylate cyclase, the key enz)nne that links many hormones and neurotransmitters with their intracellular actions. Thus antidiuretic hormone and thyroid-stimulating-hormone-sensitive adenylate cyclases are inhibited by therapeutic concentrations of the drug, which frequently leads to enhanced diuresis, h)rpoth)n oidism and even goitre. Aldosterone synthesis is increased following chronic lithium treatment and is probably a secondary consequence of the enhanced diuresis caused by the inhibition of antidiuretic-hormone-sensitive adenylate cyclase in the kidney. There is also evidence that chronic lithium treatment causes an increase in serum parathyroid hormone levels and, with this, a rise in calcium and magnesium concentrations. A decrease in plasma phosphate and in bone mineralization can also be attributed to the effects of the drug on parathyroid activity. Whether these changes are of any clinical consequence is unclear. 

The anticonvulsant properties of the drug would appear to be due to its ability to inhibit fast sodium channels, which may be unrelated to its psychotropic effects. Like lithium, it has been shown to decrease the release of noradrenaline and reduce noradrenaline-induced adenylate cyclase activity unlike lithium, it seems to have little effect on tryptophan or 5-HT levels in patients at therapeutically relevant concentrations. It also reduces dopamine turnover in manic patients and increases acetylcholine... 

Misoprostol is a stable analog of prostaglandin Ei. It reduces acid secretion by inhibiting histamine-stimulated adenyl cyclase activity in the parietal cell. 

Lithium blocks the release of thyroxine (T4) and triiodothyronine (T3) mediated by thyrotropin (Kleiner et ah, 1999). This results in a decrease in circulating T4 and T3 concentrations and a feedback increase in serum thyrotropin concentration. It also inhibits thyrotropin-stimulated adenylate cyclase activity (Kleiner et ah, 1999). Lithium has varying effects on carbohydrate metabolism. Increased and decreased glucose tolerance and decreased sensitivity to insulin have been observed (Van derVelde Gordon, 1969). In animals, lithium decreases hepatic cholesterol and fatty acid synthesis. 

---