Ryanodine receptor regulates endogenous cannabinoid mobilization in the hippocampus.
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.
Department of Physiology, University of Maryland, Baltimore, Maryland, USA. Masako.Isokawa@utb.edu
Masako
M
Isokawa
Bradley E
BE
Alger
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001692:Biological Transport / Q000187:drug effects / Q000528:radiation effects; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D003952:Diagnostic Imaging / Q000379:methods; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D066298:In Vitro Techniques; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D013997:Time Factors
D063385:Cannabinoid Receptor Modulators; D000697:Central Nervous System Stimulants; D004791:Enzyme Inhibitors; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; D002110:Caffeine; D002118:Calcium