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 A₂ (PLA₂) 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 PLA₂ 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.