Abstract
Endocannabinoids (eCB) mediate retrograde signal and modulate transmission efficacy at various central synapses. Release of eCB is induced by either depolarization or activation of Gq/11-coupled receptors. However it is markedly enhanced by the coincidence of depolarization and receptor activation. Phospholipase C (PLC) is involved in biosynthesis of the major eCB, 2-arachidonoylglycerol. PLCβ requires both activation of Gq/11-coupled receptors and Ca2+ for its activation. These results suggest that PLCβ is likely to mediate the enhancement of eCB release. To examine this possibility, we used cultured hippocampal neurons and recorded cannnabinoid-sensitive synaptic currents. We confirmed that the receptor-driven eCB release was absent in PLCβ1-knockout mice. We found that this PLCβ1-mediated eCB release was dependent on physiological levels of intracellular Ca2+ concentration ([Ca2+]i) and markedly enhanced by depolarization-induced [Ca2+]i elevation. We measured PLCβ1 activity in intact neurons by using exogenous TRPC6 channel as a biosensor for the PLC product diacylglycerol. The receptor-driven TRPC6 currents were absent in PLCβ1-knockout mice, showed a similar [Ca2+]i dependence to that of receptor-driven eCB release and were augmented by depolarization-induced [Ca2+]i elevation. These results indicate that PLCβ1 serves as a coincidence detector through its Ca2+ dependency for triggering eCB release in hippocampal neurons. [Jpn J Physiol 55 Suppl:S153 (2005)]
