Ryanodine Receptor Regulates Endogenous Cannabinoid Mobilization in the Hippocampus

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Abstract
Endogenous cannabinoids (eCBs) are produced and mobilized in a cytosolic calcium ([Ca2+]i)–dependent manner, and they regulate excitatory and inhibitory neurotransmitter release by acting as retrograde messengers. An indirect but real-time bioassay for this process on GABAergic transmission is DSI (depolarization-induced suppression of inhibition). The magnitude of DSI correlates linearly with depolarization-induced increase of [Ca2+]ithat is thought to be initiated by Ca2+influx through voltage-gated Ca2+channels. However, the identity of Ca2+sources involved in eCB mobilization in DSI remains undetermined. Here we show that, in CA1 pyramidal cells, DSI-inducing depolarizing voltage steps caused Ca2+-induced Ca2+release (CICR) by activating the ryanodine receptor (RyR) Ca2+-release channel. CICR was reduced, and the remaining increase in [Ca2+]iwas less effective in generating DSI, when the RyR antagonists, ryanodine or ruthenium red, were applied intracellularly, or the Ca2+stores were depleted by the Ca2+-ATPase inhibitors, cyclopiazonic acid or thapsigargin. The CICR-dependent effects were most prominent in cultured or immature acute slices, but were also detectable in slices from adult tissue. Thus we suggest that voltage-gated Ca2+entry raises local [Ca2+]isufficiently to activate nearby RyRs and that the resulting CICR plays a critical role in initiating eCB mobilization. RyR may be a key molecule for the depolarization-induced production of eCBs that inhibit GABA release in the hippocampus.