Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serotonin 5-HT1A receptors have been reported to be negatively coupled to muscarinic receptor-stimulated phosphoinositide turnover in the rat hippocampus. In the present study, we have investigated further the pharmacological specificity of this negative control and attempted to elucidate the mechanism whereby 5-HT1A receptor activation inhibits the carbachol-stimulated phosphoinositide response in immature or adult rat hippocampal slices. Various 5-HT1A receptor agonists were found to inhibit carbachol (10 microM)-stimulated formation of total inositol phosphates in immature rat hippocampal slices with the following rank order of potency (IC50 values in nM): 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (11) greater than ipsapirone (20) greater than gepirone (120) greater than RU 24969 (140) greater than buspirone (560) greater than 1-(m-trifluoromethylphenyl)piperazine (1,500) greater than methysergide (5,644); selective 5-HT1B, 5-HT2, and 5-HT3 receptor agonists were inactive. The potency of the 5-HT1A receptor agonists investigated as inhibitors of the carbachol response was well correlated (r = 0.92) with their potency as inhibitors of the forskolin-stimulated adenylate cyclase in guinea pig hippocampal membranes. 8-OH-DPAT (10 microM) fully inhibited the carbachol-stimulated formation of inositol di-, tris-, and tetrakisphosphate but only partially antagonized (-40%) inositol monophosphate production. The effect of 8-OH-DPAT on carbachol-stimulated phosphoinositide turnover was not prevented by addition of tetrodotoxin (1 microM), by prior destruction of serotonergic afferents, by experimental manipulations causing an increase in cyclic AMP levels (addition of 10 microM forskolin), or by changes in membrane potential (increase in K+ concentration or addition of tetraethylammonium). Prior intrahippocampal injection of pertussis toxin also failed to alter the ability of 8-OH-DPAT to inhibit the carbachol response. Carbachol-stimulated phosphoinositide turnover in immature rat hippocampal slices was inhibited by the protein kinase C activators phorbol 12-myristate 13-acetate (10 microM) and arachidonic acid (100 microM). Moreover, the inhibitory effect of 8-OH-DPAT on the carbachol response was blocked by 10 microM quinacrine (a phospholipase A2 inhibitor) but not by BW 755C (100 microM), a cyclooxygenase and lipoxygenase inhibitor. These results collectively suggest that 5-HT1A receptor activation inhibits carbachol-stimulated phosphoinositide turnover by stimulating a phospholipase A2 coupled to 5-HT1A receptors, leading to arachidonic acid release. Arachidonic acid could in turn activate a gamma-protein kinase C with as a consequence an inhibition of carbachol-stimulated phosphoinositide turnover. This inhibition may be the consequence of a phospholipase C phosphorylation and/or a direct effect on the muscarinic receptor.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Potential mechanisms involved in the negative coupling between serotonin 5-HT1A receptors and carbachol-stimulated phosphoinositide turnover in the rat hippocampus. 184 78

Exposure of HeLa cells stably expressing cloned human 5-hydroxytryptamine (5-HT)1A receptors (HA7 cells) to the agonist 8-hydroxy-2-(di-N-propylamino)-tetralin (8-OH-DPAT) results in a loss of high-affinity binding sites and a desensitization of receptor-adenylate cyclase coupling, as measured by 5-HT1A-mediated inhibition of forskolin-stimulated adenylate cyclase activity. These responses can also be observed after exposure to forskolin, which activates cyclic AMP-dependent protein kinase A or after treatment with known activators of protein kinase C (PKC) such as phorbol-12-myristate 13-acetate (PMA). The responses elicited by exposure to 8-OH-DPAT or PMA can be blocked completely by inhibitors of PKC and also by 24-hr exposure to PMA. Preincubation of HA7 cells with 8-OH-DPAT also stimulates hydrolysis of inositol phospholipids and the production of arachidonic acid. Inhibition of phospholipase A2 with quinacrine or by removal of extracellular Ca++ blocks the agonist-mediated loss of 5-HT1A receptor binding sites. These data demonstrate that agonist-induced down regulation of the 5-HT1A receptor occurs after stimulation of both the PKC and phospholipase A2 signaling pathways, both of which may activate PKC. The subsequent response is a loss of high-affinity ligand binding sites and functional receptor coupling to adenylate cyclase.
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PMID:Agonist-induced desensitization and loss of high-affinity binding sites of stably expressed human 5-HT1A receptors. 813 23