Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the rat brain, a number of receptors are linked to phospholipase C which catalyzes the hydrolysis of membrane inositol phospholipids; stimulation of alpha 1-adrenergic receptors, for example, increases polyphosphoinositide turnover, but stimulation of alpha 2-receptors does not. The hydrolysis of inositol phospholipids in rat cortical slices was investigated using a direct assay involving prelabeling these lipids with 3H-inositol and then measuring the formation of 3H-inositol phosphates in the presence of lithium ions. As expected, clonidine, an alpha 2-agonist, did not stimulate the formation of 3H-inositol phosphates; however, clonidine antagonized the ability of noradrenaline to stimulate 3H-inositol phosphate formation. This effect was not blocked by antagonists of alpha 2, 5HT2, H2, or muscarinic receptors. Clonidine did not affect carbachol-stimulated 3H-inositol phosphate formation.
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PMID:Inhibition of polyphosphoinositide turnover in rat cerebral cortex by clonidine. 255 43

Within the short period of 5 years, the availability of a variety of specific radioligands has allowed the resolution of alpha 1- and alpha 2-adrenergic receptor populations in many different tissues and enabled researchers to begin investigations of the mechanisms of regulation and coupling of alpha 1 and alpha 2 receptors to their different cellular effector systems. Binding data have demonstrated that the pharmacological properties of each type of alpha receptor are, in general, similar across tissues and species, although there are some differences in the relative affinities of antagonist drugs. Further attempts to subclassify alpha 1 and alpha 2 receptors may be expected in the future. The historical development of the interpretation of [3H]clonidine binding is of interest in this regard. [3H]Clonidine was proposed to label the "agonist state" of the alpha receptor, and then to label alpha 2 receptors. It is now thought that it labels the agonist state of alpha 2 receptors. Might it actually label a subpopulation of alpha 2 receptors or just the agonist state of that subpopulation? Alpha-1 receptors by and large appear to occur in a single-affinity state with respect to both agonists and antagonists. By comparison, alpha 2 receptors may exist in multiple-affinity states reflecting the ability of the alpha 2 binding site protein to complex to additional membrane proteins which themselves are receptors for the physiological substrates GTP, Na+, Mg2+, and possibly Ca2+-calmodulin. Binding studies have also strongly indicated that alpha 2 receptors in most, if not all, tissues are probably coupled in an inhibitory manner to adenylate cyclase, as has been demonstrated in platelets, adipocytes, and NG 108-15 cells. Clearly the present status of alpha-receptor research has left many questions unresolved. We still have no idea what membrane effector system and associated second messenger is coupled to the alpha 1 receptor. The prevailing belief is that Ca2+ and the membrane Ca2+ channel fulfill these roles. However, others have suggested that phosphoinositide turnover represents the proximal receptor response, and indeed a membrane-bound phospholipase C may play an analogous role to adenylate cyclase for other adrenergic receptors (Putney et al., 1980). There is, however, some evidence that in some situations alpha 1 receptors may directly stimulate adenylate cyclase, and guanine nucleotide modulation of agonist affinities at alpha 1-receptor sites has been reported. The significance of these data and reported modulatory effects of Na+ at alpha 1 receptors (Glossmann and Presek, 1979; Glossmann et al., 1981) is still to be resolved.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Characterization of alpha 1- and alpha 2-adrenergic receptors. 631 99

The agonist profiles for Ca++ elevations mediated by the human alpha-2 adrenoceptor subtypes alpha-2A, alpha-2B and alpha-2C were compared in the clones of Chinese hamster ovary cells expressing comparable numbers of receptors. No difference was seen between the different clones with respect to the maximum Ca++ mobilizations or the concentrations producing half-maximal stimulation in response to noradrenaline. Ca++ elevations were sensitive to phospholipase C inhibitor U-73122 (1-[6-([17beta]-3-methoxyestra-1,3, 5[10]-trien-17-yl)aminohexyl]-1H-pyrrole-2,5-dione) and pertussis toxin-pretreatment. Although noradrenaline was equally potent and active in all the clones, marked differences in the response to the other agonists were seen. UK14,304 (5-bromo-N-[4, 5-dihydro-1H-imidazol-2-yl]-6-quinoxalinamine) was a full agonist (when compared to noradrenaline) for alpha-2A and alpha-2C, D-medetomidine ([+]-[S]-[4-(1-[2, 3-dimethylphenyl]ethyl)-1H-imidazole]HCl) was a full agonist for alpha-2B and alpha-2C and oxymetazoline (3-[(4, 5-dihydro-1H-imidazol-2-yl-)methyl]-6-[1,1-dimethylethyl]-2, 4-dimethylphenol HCl) was a full agonist only for alpha-2B receptors. Clonidine (2-[2,6-dichloroaniline]-2-imidazoline HCl) was a partial agonist in all the cases; almost no response to this ligand was obtained in the alpha-2B-expressing cells. When the Ca++ responses are compared to the previously published results on cAMP inhibition in Chinese hamster ovary cells, clonidine seems to be significantly less efficacious in elevating Ca++ than in decreasing cAMP.
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PMID:Ligand- and subtype-selective coupling of human alpha-2 adrenoceptors to Ca++ elevation in Chinese hamster ovary cells. 980 94

Although clonidine is known to affect vascular smooth muscle, its effects on airway smooth muscle are not fully understood. This study was designed to examine the effects of clonidine on carbachol-induced contractile and phosphatidylinositol responses of rat trachea. Clonidine, at a dose of 100 microM or greater, attenuated carbachol-induced contraction and the accumulation of carbachol-induced inositol monophosphate (IP1). Clonidine also attenuated the accumulation of aluminium fluoride-induced IP1. The concentration-effect relationship of IP1 accumulation was similar to that of carbachol-induced contraction; r = 0.797, P < 0.001. These results suggest that clonidine attenuates contractile responses, at least in part, through the inhibition of phospholipase C (coupled with G-proteins) in phosphatidylinositol responses.
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PMID:Clonidine attenuates the carbachol-induced contractile and phosphatidylinositol responses of rat trachea. 1119 82

There are both post- and pre-synaptic vascular imidazoline (IM) binding sites. The importance of direct IM actions and that of peripheral imidazoline receptors (IRs) are shadowed by the central effects of IMs and by their interaction with alpha 2 adrenoceptors. Since the discovery of clonidine the many studies on IMs have been focused on their hypotensive effect, with rilmenidine and moxonidine as representative drugs. Formerly called IM preferring alpha 2 or IM/guanidium sites, the IRs (idazoxan-sensitive) are the plasmalemmal I1 (clonidine-sensitive) and the various I2 (one structure identified as MAO). I1 signaling includes activation of phosphatidylcholine-selective phospholipase C and inhibition of some ligand-gated channels. Inhibitory IRs on postganglionic sympathetic terminals, are not alpha 2, H3, I1 or I2. Some IMs directly affect CaL, while others inhibit K+ efflux. Clonidine-displacing substances including agmatine are endogenous ligands at IRs and alpha 2 and may participate in arterial pressure control. Beside few speculations, the roles of vascular IRs are largely unknown.
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PMID:Implications of imidazolines and imidazoline receptors role at the vascular level. 1208 57

Adrenergic agonists, through activation of intestinal epithelial alpha2-adrenergic receptors (alpha2AR), inhibit electrolyte secretion and promote absorption. The mechanisms of action to promote basal Na(+) absorption and inhibit stimulated secretion are not understood completely. The effects of alpha2-agonists on Na(+) transport were studied in a cell line, Caco2-3B, derived from the Caco2 cell line engineered to permanently express human alpha2A-adrenergic receptors. Serosal, but not mucosal, addition of the alpha2AR agonist N-(2,6-dichlorophenyl)-4,5-dihydro-1H-imidazol-2-amine (clonidine) increased Caco2-3B apical (22)Na(+) uptake, an effect not seen in the Caco2 parent line that lacks alpha2AR expression. This effect was blocked by the alpha2AR antagonist 17alpha-yohmban-16alpha-carboxylic acid methyl ester (yohimbine). Increased Na(+) uptake was paralleled by increased apical surface abundance of the sodium/hydrogen exchangers NHE2 and NHE3. No changes in total cell NHE2 and NHE3 expression were observed. Clonidine also inhibited both cAMP and Ca(2+)-induced decreases in apical Na(+) uptake and apical membrane NHE2 and NHE3 endocytosis stimulated by these agents. alpha2AR actions were mediated via stimulation of phospholipase C, and metabolism of arachidonic acid by an epoxygenase activity followed epidermal growth factor release and activation of the epidermal growth factor receptor, resulting in phosphatidylinositol-3-kinase and Akt stimulation. In summary, activation of intestinal epithelial alpha2AR significantly blocks the inhibition of apical Na(+) transporters by cAMP- and Ca(2+)-mediated pathways and also directly increases apical sodium/hydrogen exchange activities. By both blocking electrolyte secretion and promoting absorption, alpha2-agonists could be potent antidiarrheal agents that could directly counteract the actions of toxigenic pathogens and other secretagogues causing secretory diarrhea.
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PMID:Alpha2-adrenergic receptors attenuate secretagogue-induced endocytosis and promote exocytosis of intestinal NHE2 and NHE3. 1955 51