Temporal Regulation of Agonist Efficacy at 5-Hydroxytryptamine (5-HT)1A and 5-HT1BReceptors

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Abstract
Coactivation of purinergic (P2Y) receptors reduces agonist efficacy at serotonin1B (5-HT1B), but not 5-HT1A receptors. Herein, we report that pretreatment for 5 min with the P2Y receptor agonist ATP reduced agonist responsiveness at the 5-HT1A, but not at the 5-HT1B, receptor. The effect of ATP pretreatment on the 5-HT1A receptor response rapidly reversed within a 10 min time frame between P2Y receptor and 5-HT1Areceptor activation. ATP pretreatment effects on 5-HT1Aagonist responsiveness were blocked by the protein kinase inhibitors staurosporine and bisindolylmaleimide, suggesting that the ATP-mediated temporal regulation involves activation of protein kinase C (PKC). Moreover, the temporal effect of ATP was blocked by incubation with 1% ethanol, suggesting that consequences of phospholipase D (PLD) activation play a role. ATP pretreatment blocked the inhibitory effect produced by 5-HT2C receptor activation on the 5-HT1A, but not the 5-HT1B, receptor response, suggesting that the 5-HT1A receptor itself was the target for PLD/PKC action. Finally, ethanol did not block the reduction in responsiveness of the 5-HT1A receptor system produced by activation of PKC with phorbol ester treatment, suggesting that PKC activation lies downstream of PLD. Taken together, these data suggest that activation of P2Y receptors can reduce responsiveness of the 5-HT1A receptor system via a PLD/PKC-dependent mechanism that is highly dependent upon the temporal pattern of receptor activation. Moreover, this work underscores the importance of time as a variable in receptor signaling cross talk and serves to further illustrate differences between the 5-HT1A and 5-HT1B receptor systems.