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Ryanodine Receptor Regulates Endogenous Cannabinoid Mobilization in the Hippocampus

Department of Physiology, University of Maryland, Baltimore, Maryland

Submitted 21 September 2005; accepted in final form 2 February 2006

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⁺]_i that 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⁺]_i was 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⁺]_i sufficiently 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.

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