Mechanisms of regulation of agonist efficacy at the 5-HT(1A) receptor by phospholipid-derived signaling components.
The 5-hydroxytryptamine (5-HT)(1A) receptor system plays a prominent role in a variety of physiological functions and behaviors and regulation of the responsiveness of this receptor system has been implicated in the therapeutic mechanism of action of the selective serotonin reuptake inhibitor class of antidepressant drugs. Here we report that the responsiveness of the 5-HT(1A) receptor system is regulated by consequences of activation of the phospholipase A(2) (PLA(2)) and phospholipase C effector pathways. In Chinese hamster ovary cells stably expressing the human 5-HT(1A) receptor, 5-HT(1A) receptor-mediated inhibition of forskolin-stimulated cAMP accumulation was reduced by a cyclooxygenase-dependent arachidonic acid (AA) metabolite produced in response to exogenously applied AA or activation of PLA(2) directly with melittin or indirectly by receptor activation. This effect of the AA metabolite was sensitive to the activation state of adenylyl cyclase suggesting that the target of the AA metabolite-induced reduction in 5-HT(1A) responsiveness was adenylyl cyclase. Activation of protein kinase C with a phorbol ester also reduced 5-HT(1A) receptor function. In contrast, increases in intracellular calcium levels via a calcium ionophore or thapsigargin enhanced 5-HT(1A) responsiveness. The net effect of activation of phospholipid-coupled receptors on 5-HT(1A) agonist efficacy depended upon the relative capacity to produce these positive (calcium) and negative (AA) regulators. These data demonstrate that the responsiveness of the 5-HT(1A) receptor system can be enhanced or depressed by consequences of activation of phospholipid-coupled receptor systems. An understanding of the cellular mechanisms for regulation of 5-HT(1A) function may lead to novel targets for development of psychotherapeutic drugs.
Evans
K L
KL
Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas, USA.
Cropper
J D
JD
Berg
K A
KA
Clarke
W P
WP
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism / Q000494:pharmacology; D016466:CHO Cells; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008555:Melitten / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D010741:Phospholipases A / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014162:Transfection; D010738:Type C Phospholipases / Q000378:metabolism
D010703:Phorbol Esters; D010743:Phospholipids; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D005576:Colforsin; D008555:Melitten; D016718:Arachidonic Acid; D002772:Cholera Toxin; D000242:Cyclic AMP; D011493:Protein Kinase C; D010741:Phospholipases A; D010738:Type C Phospholipases; D000262:Adenylyl Cyclases; D015232:Dinoprostone