Temporal regulation of agonist efficacy at 5-hydroxytryptamine (5-HT)1A and 5-HT 1B receptors

• Published in: The Journal of pharmacology and experimental therapeutics 2003-01, Vol.304 (1), p.200
• Main Authors: Berg, Kelly A, Evans, Kenda L J, Cropper, Jodie D, Clarke, William P
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - pharmacology; Animals; CHO Cells; Cricetinae; Cyclic AMP - antagonists & inhibitors; Cyclic AMP - metabolism; Enzyme Activation - physiology; Phorbol Esters - pharmacology; Phospholipase D - metabolism; Phospholipases A - metabolism; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - physiology; Receptor, Serotonin, 5-HT1B; Receptors, Purinergic P2 - drug effects; Receptors, Serotonin - drug effects; Receptors, Serotonin, 5-HT1; Serotonin Receptor Agonists - pharmacology; Signal Transduction - physiology; Time Factors; Transfection
• ISSN: 0022-3565

Coactivation of purinergic (P 2Y) receptors reduces agonist efficacy at serotonin 1B (5-HT 1B), but not 5-HT 1A receptors. Herein, we report that pretreatment for 5 min with the P 2Y receptor agonist ATP reduced agonist responsiveness at the 5-HT 1A, but not at the 5-HT 1B, receptor. The effect of ATP pretreatment on the 5-HT 1A receptor response rapidly reversed within a 10 min time frame between P 2Y receptor and 5-HT 1A receptor activation. ATP pretreatment effects on 5-HT 1A agonist 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-HT 2C receptor activation on the 5-HT 1A, but not the 5-HT 1B, receptor response, suggesting that the 5-HT 1A receptor itself was the target for PLD/PKC action. Finally, ethanol did not block the reduction in responsiveness of the 5-HT 1A 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 P 2Y receptors can reduce responsiveness of the 5-HT 1A 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-HT 1A and 5-HT 1B receptor systems.