CB₁ cannabinoid receptor‐dependent and ‐independent inhibition of depolarization‐induced calcium influx in oligodendrocytes

Abstract

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.

Cannabidiol and Other Cannabinoids Reduce Microglial Activation In Vitro and In Vivo: Relevance to Alzheimer's Disease

“…Indeed, an increase in extracellular ATP, released by dying neurons and glia, can interact with purinergic receptors, increase [Ca 2ϩ ] i , and activate microglia (Fä rber and Kettenmann, 2006). On the other hand, cannabinoid agonists have been shown to inhibit calcium responses in a variety of cells, including glial cells (Mato et al, 2009).…”

P2X7 receptors mediate ischemic damage to oligodendrocytes

“…Immunostaining of O 4 was performed in live oligodendrocytes as previously described (Mato et al, 2009) using a mouse monoclonal antibody to O4 generously provided by Dr. C. Thomson (1:10, hybridoma supernatant). Oligodendroglial expression of pannexins was examined by conventional immunocytochemistry as previously described (Matute et al, 2007) using primary antibodies to pannexin 1 (1:500; Chemicon) and 2 (1 lg/ mL; Abcam).…”

A Basal Tone of 2-Arachidonoylglycerol Contributes to Early Oligodendrocyte Progenitor Proliferation by Activating Phosphatidylinositol 3-Kinase (PI3K)/AKT and the Mammalian Target of Rapamycin (MTOR) Pathways

“…However, there is limited information on the action of endocannabinoids in oligodendrocytes, the myelinating cells of CNS. Early studies about the distribution of CB1 receptors in the brain revealed enrichment in specific white matter areas (Herkenham et al 1991), and subsequent reports described CB1 receptors in oligodendrocyte progenitor cells (OPCs) derived from the optic nerve and cerebral cortex and in A2B5 + glial progenitor cells resident in the adult human subcortical white matter (Molina-Holgado et al 2002;Mato et al 2009;Sim et al 2006). More recent reports of our laboratory showed that cannabinoid agonists increase the generation of glial precursors in the period of post-natal myelination and enhance the expression of myelin basic protein in the subcortical white matter of neonatal rat brain (Arevalo-Martín et al 2007).…”