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

During secondary aggregation, platelets release 5-hydroxytryptamine (5-HT) from their dense granule stores concurrent with arachidonic acid (AA) metabolism. To examine the hypothesis that released 5-HT has a modulatory effect on the metabolism of AA by platelets, we incubated nonaggregating washed human platelets with 5-HT in the presence of [3H]AA. Stimulation with 10(-4) M 5-HT, followed by incubation with 3 microM AA and 1 microCi [3H]AA for 5 min, resulted in a decrease in the formation of thromboxane B2 (TxB2) and 12-hydroxyheptadecatrienoic acid (HHT, P less than 0.05). The same treatment conditions and stimulation with 10(-7) to 10(-4) M 5-HT resulted in an elevation of 12-hydroxyeicosatetraenoic acid (12-HETE) formation (P less than 0.05). Treatment with the monoamine uptake inhibitor imipramine (20 microM) further increased the stimulation of 12-HETE formation observed in the presence of 10(-4) M 5-HT, suggesting that 5-HT may act at the platelet surface. A 5-HT1A receptor agonist, 8-hydroxy-dipropylaminotetralin (DPAT, 10(-6) to 10(-4) M) stimulated the formation of platelet cyclooxygenase (CO) products, whereas (+/-)1-(2,5-dimethoxy-4-iodo phenyl)-amino propane hydrochloride (DOI, 10(-6) to 10(-4) M), a 5-HT2 receptor agonist, had no significant effect on CO product formation. In addition, the 5-HT2 receptor antagonist ketanserin (10(-7) M) did not block the changes in CO or lipoxygenase metabolism induced by 5-HT. Since both DOI and DPAT stimulated 12-HETE formation whereas ketanserin was unable to reverse the 5-HT-enhanced 12-HETE formation, it seems unlikely that the stimulation of a 5-HT2 receptor is responsible for this action of 5-HT on platelets. We conclude that 5-HT depresses CO product formation while increasing 12-HETE formation through interaction with a platelet serotonergic binding site other than the 5-HT2 receptor.
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PMID:5-Hydroxytryptamine and the metabolism of arachidonic acid by the lipoxygenase and cyclooxygenase of washed human platelets. 214 82

1. An inwardly rectifying K+ current activated by serotonin (5-HT) was recorded from acutely isolated adult dorsal raphe (DR) neurones using the whole-cell recording mode of the patch clamp technique. 2. The 5-HT-induced K+ current (I5-HT) was only visible at an [K+]0 > 5 mM and it was observed in 69% of the cells. 3. The reversal potential for I5-HT was close to the potassium equilibrium potential and was shifted by 51 mV per 10-fold change in [K+]0 indicating that I5-HT was carried predominantly by K+. The chord conductance of I5-HT at -90 mV was proportional to the external [K+] raised to a fractional power. 4. A dose-response relationship revealed that I5-HT was activated with an ED50 of 30 nM. Ba2+ (0.1 mM) blocked I5-HT completely. Spiperone reversibly antagonized the response to 5-HT and 8-OHDPAT (8-hydroxy-2-(di-n-propylamino)tetralin) mimicked the response indicating that the receptor activated was of the 5-HT1A subtype. 5. The response to 5-HT was largely prevented by in vitro pretreatment of the cells with pertussis toxin (PTX) indicating the involvement of a PTX-sensitive G-protein in the transduction mechanism. 6. cAMP and lipoxygenase metabolites, both implicated in the modulation of similar currents in other preparations, were found not to alter the effectiveness of 5-HT. 7. Glibenclamide and tolbutamide, blockers of the ATP-regulated K+ channel, did not reduce the effect of 5-HT in DR neurones. 8. These results show that in acutely isolated adult DR neurones 5-HT activates an inwardly rectifying K+ current and this involves a PTX-sensitive G-protein in the transduction pathway which may interact with the K+ channel directly.
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PMID:Whole-cell recordings of inwardly rectifying K+ currents activated by 5-HT1A receptors on dorsal raphe neurones of the adult rat. 827 Dec 4