Calcium channels in rat horizontal cells regulate feedback inhibition of photoreceptors through an unconventional GABA- and pH-sensitive mechanism

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Horizontal cells send inhibitory feedback to photoreceptors, helping form antagonistic receptive fields in the retina, but the neurotransmitter and the mechanisms underlying this signalling are not known. Since the proteins responsible for conventional Ca2+-dependent release of GABAergic synaptic vesicles are present in mammalian horizontal cells, we investigated this conventional mechanism as the means by which horizontal cells inhibit photoreceptors. Using Ca2+ imaging in rat retinal slices, we confirm that horizontal cell depolarization with kainate inhibits and horizontal cell hyperpolarization with NBQX disinhibits the Ca2+ signals produced by pH-sensitive activation of voltage-gated calcium channels (Ca channels) in photoreceptors. We show that while 100 μm Co2+ reduces photoreceptor Ca2+ signals, it disinhibits them at 10 μm, an effect reminiscent of earlier studies where low [Co2+] eliminated feedback. The low [Co2+] disinhibition is pH sensitive. We localized L-, N- and P/Q-type Ca channels in rat horizontal cells, and showed that both the N-type Ca channel blocker ω-conotoxin GVIA and the P/Q-type Ca channel blocker ω-agatoxin IVA increased Ca2+ signals in photoreceptors in a pH-sensitive manner. Pronounced actions of GABAergic agents on feedback signals to photoreceptors were observed, and are pH sensitive, but are inconsistent with direct inhibition by GABA of photoreceptor [Ca2+]. Patch-clamp studies revealed that GABA activates a conductance having high bicarbonate permeability in isolated horizontal cells, suggesting that the commonality of pH sensitivity throughout the results could arise from a GABA autofeedback action in horizontal cells. This could change cleft pH with concomitant inhibitory influences on photoreceptor Ca channels.

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