Fig. 7. Schematic representation of photoreceptor Ca²⁺ flux under different experimental conditions.

a The phototransduction cascade is compartmentalised to the photoreceptor outer segments, which harbour cyclic nucleotide-gated channel (CNGC) and Na⁺/Ca²⁺/K⁺ exchanger (NCKX). The connecting cilium links outer to inner segment, which holds almost all mitochondria and the ATP-driven Na⁺/K⁺ exchanger (NKX). The cell body harbours the nucleus as well as Ca²⁺-release activated channel (CRAC), plasma membrane Ca²⁺-ATPase (PMCA), and voltage-gated Ca²⁺ channels (VGCC). PMCA and VGCC are also found in the synapse. b In the dark, the flux of Na⁺ and Ca²⁺ ions across the photoreceptor membrane (i.e., the dark current) keeps the cell in a continuously depolarised state. The Ca²⁺ ions enter the outer segment via CNGC and exits via NCKX. The Na⁺ gradient needed to drive NCKX is maintained by the ATP-dependent NKX in the inner segment. At the same time, in the photoreceptor cell body and synapse, VGCC allows for Ca²⁺ influx, mediating synaptic glutamate release. In the cell body and synapse, Ca²⁺ is extruded by the ATP-dependent PMCA. c In light, CNGC closes, while Ca²⁺ continues to exit the cell via NCKX, leading to photoreceptor hyperpolarization. This in turn closes VGCC, ending synaptic glutamate release. d In rd1 photoreceptors, high cGMP continuously opens CNGC, representing a situation of “constant darkness”. Excessive NKX activity in rd1 may cause a depletion of ATP, preventing Ca²⁺ extrusion via PMCA. e L-cis-diltiazem (red lines) blocks predominantly CNGC, with an additional block on VGCC at high concentrations. This resembles a situation of “constant light” and may cause a depletion of intracellular Ca²⁺ and secondary Ca²⁺ influx via activation of CRAC. f D-cis-diltiazem (blue lines) inhibits predominantly VGCC, with a partial block on CNGC at high concentrations.