Inhibition of adenylate cyclase

Lithium. In the lithium carbonate treatment of certain psychotic states, a low incidence (3.6%) of hypothyroidism and goiter production have been observed as side effects (6,36) (see Psychopharmacologicalagents). It has been proposed that the mechanism of this action is the inhibition of adenyl cyclase. Lithium salts have not found general acceptance in the treatment of hyperthyroidism (see Lithiumand lithium compounds). 

The OP group of receptois share common effector mechanisms. All receptois couple via pertussis toxin-sensitive Go and Gi proteins leading to (i) inhibition of adenylate cyclase (ii) reduction of Ca2+ currents via diverse Ca2+ channels (hi) activation of inward rectifying K+ channels. In addition, the majority of these receptors cause the activation of phospholipase A2 (PLA2), phospholipase C 3 (PLC 3), phospholipase D2 and of MAP (mitogen-activated protein) kinase (Table 3). 

Kaminski NE, Koh WS, Yang KH, Lee M, Kessler FK. Suppression of the humoral immune response by cannabinoids is partially mediated through inhibition of adenylate cyclase by a pertussis toxin-sensitive G-protein-coupled mechanism. Biochem Pharmacol 1994 48 1899-1908. 

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. 

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

Initially, it was proposed that the 5-HTjb receptor is located exclusively in the brain of the rat and some other rodents, whereas the 5-HTid receptor, a close species homolog, is specific to the guinea pig and higher mammalian species, including humans (Waeber et al., 1989). However, recent studies have characterized the 5-HTiB receptor also in the human brain (Bidmon et al., 2001 Varnas et al., 2005). The 5-HT, B receptor is linked to the inhibition of adenylate cyclase, and is located at presynaptic (5-HT axon terminals) and postsynaptic... 

H2 receptors are associated with adenylate cyclase, and stimulation of these receptors increases the cytosolic concentration of cAMP and activation of cAMP-dependent protein kinase. Although inhibition of adenylate cyclase has been suggested as the intracellular signaling mechanism associated with H receptors, this has not been completely substantiated. 

The effects of Li+ upon hematopoiesis have been proposed to be due to two different systems modification of the activity of the membrane Na+/K+-ATPase, and the inhibition of adenylate cyclase. Monovalent cation flux, in particular Na+ transport, is known to influence the differentiation and proliferation of hematopoietic stem cells. For instance, ouabain, an effective inhibitor of the membrane Na+/K+-ATPase, blocks the proliferation of lymphocytes and has been shown to attenuate the Li+-induced proliferation of granulocyte precursors [208]. Conversely, Li+ can reverse the actions of amphotericin and monensin, which mediate Na+ transport and which inhibit CFU-GM, CFU-E, and CFU-MK colony formation in the absence of Li+ [209]. Therefore, the influence of Li+ upon normal physiological cation transport—for example, its influence upon Na+/K+-ATPase activity—may be partly responsible for the observed interference in hematopoiesis. 

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. 

Hewlett AC, Fleming RM, Cannabinoid inhibition of adenylate cyclase. Pharmacology of the response in neuroblastoma cell membranes. Mol Pharmacol 26 532-538, 1984. 

Hewlett AC, Qualy JM, Khachatrian LL, Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic dtvegs. Mol Pharmacol 29 307—313, 1986. 

The second-messenger linkage of postsynaptic 5-HTj receptors has been connected in various neurons with either inhibition of adenylate cyclase, stimulation of adenylate cyclase, or inhibition of phosphoinositide turnover (Harrington et al. 1992]. 

Katada T, Gillman AG, Watanabe Y, et al Protein C phosphorylates the inhibitory guanine-nucleotide-binding regulatory component and apparently suppresses its function in hormonal inhibition of adenylate cyclase. Eur J Biochem 151 431-437, 1985... 

Since they are linked to G-proteins, opioid receptors affect intracellular Ca and protein phosphorylation. Another principal biochemical effect of opiates is the inhibition of adenylate cyclase (AC), which decreases cAMP production. 

Opioids induce an inhibitory effect on gastrointestinal motility and fluid secretion (Kromer, 1990). The effect is peripherally and centrally mediated. The peripheral component is related to p- and K-receptors in intestinal organs, which are densely equipped with opioid receptors. They are located at parasympathic ganglia and inhibit the release of acetylcholine, which stimulates the contraction of smooth muscles. Inhibition of the intestinal fluid secretion is mediated via inhibition of adenylate cyclase. The intestinal effects of opioids extend to all parts of the gut and results in inhibition of stomach emptying and inhibition of secretion and motility of duodenum, jejunum, colon and rectum. 

Activation of the phosphodiesterase by light requires the presence of GTP and is associated with the binding of GTP to another protein, transducin. Transducin is a member of the family of G proteins that participate in the activation or inhibition of adenylate cyclase by hormones in other tissues (see chapter 24). Like other G proteins, transducin consists of three subunits, a, (3, and y (fig. S2.12). In the resting state, the a subunit contains a molecule of bound GDP. When rhodopsin is transformed to metarhodopsin II by light, it interacts with transducin, causing GTP to displace the bound GDP. Once GTP is attached, the a subunit probably separates from the (3 and y subunits and binds to an inhibitory subunit of the phosphodiesterase. The removal of the inhibitory component activates the phosphodiesterase. 

Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005) An endocannabinoid mechanism for stress-induced analgesia. Nature 435(7045) 1108-12 Howlett AC, Qualy JM, Khachatrian LL (1986) Involvement of Gi in the inhibition of adenylate cyclase by cannabimimetic drugs. Mol Pharmacol 29(3) 307-13 Hsu K-T, Storch J (1996) Fatty acid transfer from liver and intestinal fatty acid-binding proteins to membranes occurs by different mechanisms. J Biol Chem 271(23) 13317—23... 

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