• Jayne R Bramley, Erin M Wiles, Patricia J Sollars, and Gary E Pickard.
• School of Veterinary Medicine and Biomedical Sciences, University of Nebraska, Lincoln, Nebraska, United States of America.
• Plos One. 2011 Jan 1; 6 (7): e22721.

BackgroundRetinal ganglion cells expressing the photopigment melanopsin are intrinsically photosensitive (ipRGCs). These ganglion cell photoreceptors send axons to several central targets involved in a variety of functions. Within the retina ipRGCs provide excitatory drive to dopaminergic amacrine cells via glutamatergic signals and ipRGCs are coupled to wide-field GABAergic amacrine cells via gap junctions. However, the extent to which ipRGCs are coupled to other retinal neurons in the ganglion cell layer via gap junctions is unclear. Carbenoxolone, a widely employed gap junction inhibitor, greatly reduces the number of retinal neurons exhibiting non-rod, non-cone mediated light-evoked Ca(2+) signals suggesting extensive intercellular coupling between ipRGCs and non-ipRGCs in the ganglion cell layer. However, carbenoxolone may directly inhibit light-evoked Ca(2+) signals in ipRGCs independent of gap junction blockade.Methodology/Principal FindingsTo test the possibility that carbenoxolone directly inhibits light-evoked Ca(2+) responses in ipRGCs, the light-evoked rise in intracellular Ca(2+) ([Ca(2+)](i)) was examined using fura-2 imaging in isolated rat ipRGCs maintained in short-term culture in the absence and presence of carbenoxolone. Carbenoxolone at 50 and 100 µM concentrations completely abolished the light-evoked rise in [Ca(2+)](i) in isolated ipRGCs. Recovery from carbenoxolone inhibition was variable.Conclusions/SignificanceWe demonstrate that the light-evoked rise in [Ca(2+)](i) in isolated mammalian ganglion cell photoreceptors is inhibited by carbenoxolone. Since the light-evoked increase in [Ca(2+)](i) in isolated ipRGCs is almost entirely due to Ca(2+) entry via L-type voltage-gated calcium channels and carbenoxolone does not inhibit light-evoked action potential firing in ipRGCs in situ, carbenoxolone may block the light-evoked increase in [Ca(2+)](i) in ipRGCs by blocking L-type voltage-gated Ca(2+) channels. The ability of carbenoxolone to block evoked Ca(2+) responses must be taken into account when interpreting the effects of this pharmacological agent on retinal or other neuronal circuits, particularly if a change in [Ca(2+)](i) is the output being measured.

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