TRPC5 is required for the NO-dependent increase in dendritic Ca2+ and GABA release from chick retinal amacrine cells

GABAergic signaling from amacrine cells (ACs) is a fundamental aspect of visual signal processing in the inner retina. We have previously shown that nitric oxide (NO) can elicit release of GABA independently from activation of voltage-gated Ca²⁺ channels in cultured retinal ACs. This voltage-independent quantal GABA release relies on a Ca²⁺ influx mechanism with pharmacological characteristics consistent with the involvement of transient receptor potential canonical (TRPC) channels TRPC4 and/or TRPC5. To determine the identity of these channels, we evaluate the ability of NO to elevate dendritic Ca²⁺ and to stimulate GABA release from cultured ACs under conditions known to alter the function of TRPC4 and 5. We find that these effects of NO are phospholipase C-dependent, have a biphasic dependence on La³⁺ and are unaffected by moderate concentrations of the TRPC4 selective antagonist ML204. Together, these results suggest that NO promotes GABA release by activating TRPC5 channels in AC dendrites. To confirm a role for TRPC5, we knocked down the expression of TRPC5 using CRISPR/Cas9-mediated gene knockdown and found that both the NO-dependent Ca²⁺ elevations and increase in GABA release are dependent upon the expression of TRPC5. These results demonstrate a novel NO-dependent mechanism for regulating neurotransmitter output from retinal ACs.

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