Abstract
Hereditary degeneration of photoreceptors has been linked to over-activation of Ca2+-permeable channels, excessive Ca2+-influx, and downstream activation of Ca2+-dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca2+-channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were very effective at blocking photoreceptor Ca2+-influx, most probably by blocking the pore of Ca2+-permeable channels. Yet, unexpectedly, this block neither reduced the activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca2+ and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca2+-independent degenerative mechanisms.
Highlights
In the retina, rod photoreceptors respond to dim light and enable night-time vision, whereas cone photoreceptors respond to bright daylight and enable colour vision
The oocyte plasma membrane: (1) Co-expression of the main subunits, rod CNGA1 and cone CNGA3, with their modulatory Influence of L-cis-diltiazem on cGMP binding subunits, CNGB1a and CNGB3, respectively, led to a strong To assess whether diltiazem influences ligand binding, we increase of cAMP efficacy in heterotetrameric vs. homotetrameric employed confocal patch-clamp fluorometry [30, 31]
5 DISCUSSION We show that diltiazem enantiomers were highly effective at blocking photoreceptor Ca2+ influx through cyclic nucleotide-gated channel (CNGC) at pathologically high cGMP concentrations, likely by blocking the channel’s pore
Summary
Rod photoreceptors respond to dim light and enable night-time vision, whereas cone photoreceptors respond to bright daylight and enable colour vision. CGMP opens the cyclic nucleotide-gated channel (CNGC), located in the photoreceptor outer segment (OS), causing influx of Ca2+ and Na+ [6]. This influx is countered by the Na+-Ca2+-K+-exchanger (NCKX) in the OS and by the ATPdriven Na+-K+-exchanger (NKX) in the photoreceptor inner segment (IS) [6]. The consequent activation of Cav1.4 (L-type) voltage-gated Ca2+-channels (VGCCs), located in the cell body and synapse, mediates further Ca2+ influx and synaptic glutamate release [7, 8]. PDE6 rapidly hydrolyses cGMP, leading to CNGC closure, Ca2+ decrease, and photoreceptor hyperpolarization.
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