CB1 cannabinoid receptor-dependent and -independent inhibition of depolarization-induced calcium influx in oligodendrocytes.
Regulation of Ca(2+) homeostasis plays a critical role in oligodendrocyte function and survival. Cannabinoid CB(1) and CB(2) receptors have been shown to regulate Ca(2+) levels and/or K(+) currents in a variety of cell types. In this study we investigated the effect of cannabinoid compounds on the Ca(2+) influx elicited in cultured oligodendrocytes by transient membrane depolarization with an elevated extracellular K(+) concentration (50 mM). The CB(1) receptor agonist arachidonoyl-chloro-ethanolamide (ACEA) elicited a concentration-dependent inhibition of depolarization-evoked Ca(2+) transients in oligodendroglial somata with a maximal effect (94+/-3)% and an EC(50) of 1.3+/-0.03 microM. This activity was mimicked by the CB(1)/CB(2) agonist CP55,940, as well as by the endocannabinoids N-arachidonoyl-ethanolamine (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), whereas the CB(2) receptor selective agonist JWH133 was ineffective. The CB(1) receptor antagonist AM251 (1 microM) also reduced the Ca(2+) response evoked by high extracellular K(+) and did not prevent the inhibition elicited by ACEA (3 microM). Nevertheless, the ability of ACEA and AEA to reduce depolarization-evoked Ca(2+) transients was significantly reduced in oligodendrocytes from CB(1) receptor knockout mice, as well as by pretreatment with pertussis toxin. Bath application of the inwardly rectifying K(+) channels (Kir channels) blockers BaCl(2) (300 microM) and CsCl(2) (1 mM) reduced the size of voltage-induced Ca(2+) influx and partially prevented the inhibitory effect of ACEA. Our results indicate that cannabinoids inhibit depolarization-evoked Ca(2+) transients in oligodendrocytes via CB(1) receptor-independent and -dependent mechanisms that involve the activation of PTX-sensitive G(i/o) proteins and the blockade of Kir channels.
Mato
Susana
S
Department of Neuroscience, Neurotek-University of the Basque Country, Technological Park, Zamudio, Bizkaia, Spain.
Alberdi
Elena
E
Ledent
Catherine
C
Watanabe
Masahiko
M
Matute
Carlos
C
D000818:Animals; D000831:Animals, Newborn; D001095:Arachidonic Acids / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology; D003511:Cyclohexanols / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D019204:GTP-Binding Proteins / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D009900:Optic Nerve / Q000166:cytology; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D001095:Arachidonic Acids; D015220:Calcium Channels; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D003511:Cyclohexanols; D063388:Endocannabinoids; D007166:Immunosuppressive Agents; D053284:Polyunsaturated Alkamides; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D019204:GTP-Binding Proteins; D002118:Calcium; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC; C078814:anandamide