Carbenoxolone Inhibition of Voltage-Gated Ca Channels and Synaptic Transmission in the Retina

Departments of 1 Physiology and Biophysics, 2 Pharmacology, and 3 Ophthalmology, Dalhousie University, Halifax, Nova Scotia B3H-4H7, Canada Submitted 13 February 2004; accepted in final form 12 March 2004 We show that carbenoxolone, a drug used to block hemichannels in the retina to test the ephaptic model of horizontal cell inhibitory feedback, has strong inhibitory effects on voltage-gated Ca channels. Carbenoxolone (100 µM) reduced photoreceptor-to-horizontal cell synaptic transmission by 92%. Applied to patch-clamped, isolated cone photoreceptors, carbenoxolone inhibited Ca channels with an EC 50 of 48 µM. At 100 µM, it reduced cone Ca channel current by 37%, reduced depolarization-evoked [Ca 2+ ] signals in fluo-4 loaded retinal slices by 57% and inhibited Ca channels in Müller cells by 52%. A synaptic transfer model suggests that the degree of block of Ca channels accounts for the reduction in synaptic transmission. These results suggest broad inhibitory actions for carbenoxolone in the retina that must be considered when interpreting its effects on inhibitory feedback. Address for reprint requests and other correspondence: S. Barnes, Depts. of Physiology and Biophysics and Ophthalmology, Dalhousie University, 5859 University Ave., Halifax, Nova Scotia B3H-4H7, Canada (E-mail: sbarnes{at}dal.ca ).