Nitric oxide promotes GABA release by activating a voltage-independent Ca2+ influx pathway in retinal amacrine cells

Retinal amacrine cells express nitric oxide synthase and produce nitric oxide (NO), making NO available to regulate the function of amacrine cells. Here, we test the hypothesis that NO can alter the GABAergic synaptic output of amacrine cells. We investigate this using whole-cell voltage clamp recordings and Ca²⁺ imaging of cultured chick retinal amacrine cells. When recording from amacrine cells receiving synaptic input from other amacrine cells, we find that NO increases GABAergic spontaneous postsynaptic current (sPSC) frequency. This increase in sPSC frequency does not require the canonical NO receptor, soluble guanylate cyclase, or presynaptic action potentials. However, removal of extracellular Ca²⁺ and buffering of cytosolic Ca²⁺ both inhibit the response to NO. In Ca²⁺ imaging experiments, we confirm that NO increases cytosolic Ca²⁺ in amacrine cell processes by activating a Ca²⁺ influx pathway. Neither the increase in sPSC frequency nor the cytosolic Ca²⁺ elevations are dependent upon Ca²⁺ release from stores. NO also enhances evoked GABAergic responses. Because voltage-gated Ca²⁺ channel function is not altered by NO, the increased evoked response is likely due to the combined effect of voltage-dependent Ca²⁺ influx adding to the NO-dependent, voltage independent, Ca²⁺ influx. Insight into the identity of the Ca²⁺ influx pathway is provided by the transient receptor potential canonical (TRPC) channel inhibitor clemizole which prevents the NO-dependent increase in sPSC frequency and cytosolic Ca²⁺ elevations. These data suggest that NO production in the inner retina will enhance Ca²⁺-dependent GABA release from amacrine cells by activating TRPC channel(s).

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