The neglected role of endocannabinoid actions at TRPC channels in ataxia

Transient receptor potential (TRP) channels are highly expressed in cells of the cerebellum including in the dendrites and somas of Purkinje cells (PCs). Their endogenous activation promotes influx of Ca2+ and Na+, resulting in depolarization. TRP channels can be activated by endogenous endocannabinoids (eCBs) and activity of TRP channels has been shown to modulate GABA and glutamate transmission. Ataxia is caused by disruption of multiple intracellular pathways which often involve changes in Ca2+ homeostasis that can result in neural cellular dysfunction and cell death. Based on available literature, alteration of transmission of eCBs would be expected to change activity of cerebellar TRP channels. Antagonists of the endocannabinoid system (ECS) including enzymes which break eCBs down have been shown to result in reductions in postsynaptic excitatory activity mediated by TRPC channels. Further, TRPC channel antagonists could modulate both pre and postsynaptically-mediated glutamatergic and GABAergic transmission, resulting in reductions in cell death due to excitotoxicity and dysfunctions caused by abnormal inhibitory signaling. Accordingly, TRP channels, and in particular the TRPC channel, represent a potential therapeutic target for management of ataxia. •Neuropathophysiology of Ataxia in cerebellum is still enigmatic.•TRP channels are highly expressed in the cerebellar cells.•The role of endocannabinoid actions at TRP channels in ataxia is likely complex.•Ataxia is caused by disruption of Ca2+ homeostasis.•Presence of TRP and CBRs suggesting a significant role for them in Ataxia.