Temporal regulation of agonist efficacy at 5-hydroxytryptamine (5-HT)1A and 5-HT 1B receptors.
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.
Berg
Kelly A
KA
Department of Pharmacology, University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA. berg@uthscsa.edu
Evans
Kenda L J
KL
Cropper
Jodie D
JD
Clarke
William P
WP
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D010703:Phorbol Esters / Q000494:pharmacology; D010739:Phospholipase D / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D044302:Receptor, Serotonin, 5-HT1B; D018048:Receptors, Purinergic P2 / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D014162:Transfection
D010703:Phorbol Esters; D044302:Receptor, Serotonin, 5-HT1B; D018048:Receptors, Purinergic P2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D011493:Protein Kinase C; D010741:Phospholipases A; D010739:Phospholipase D