Regulation of 5-HT1A and 5-HT1B receptor systems by phospholipid signaling cascades

The 5-HT_1A and 5-HT_1B receptor systems play central roles in the control of serotonergic neurotransmission and feature prominently in many behaviors and physiological functions. In addition, the regulation of these receptors and their effector mechanisms has been the focus of intense interest because of their potential importance in the therapeutic actions of anxiolytic and antidepressant drugs. Here we describe the regulation of 5-HT_1A and 5-HT_1B receptor-mediated inhibition of adenylyl cyclase activity by receptors which activate phospholipid signaling cascades. Although it might be expected that these two highly homologous Gi-coupled receptors would be regulated similarly by activation of phospholipase C (PLC) and phospholipase A₂ (PLA₂), we have found that the regulation differs markedly between these receptor systems. Further, our data suggest that the modulation of agonist efficacy at these receptor subtypes is dependent on the nature of receptor coupling to PLC and PLA₂ activation. Moreover, regulation at the level of the effector (e.g., adenylyl cyclase) appears to play a significant role in the regulation of both the 5-HT_1A and 5-HT_1B receptor systems by the PLA₂ signaling cascade. Such data illustrate multiple levels for control of biochemical signaling cascades within cells and demonstrate that although different receptors may couple to the same effector pathways, the ultimate cellular effects produced by these receptors may differ due to differential cross-talk regulation.