Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem

ABSTRACT Hereditary degeneration of photoreceptors has been linked to over-activation of Ca 2+ -permeable channels, excessive Ca 2+ -influx, and downstream activation of Ca 2+ -dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca 2+ -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 Ca 2+ -influx, most probably by blocking the pore of Ca 2+ -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 Ca 2+ and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca 2+ -independent degenerative mechanisms.