Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem
Soumyaparna Das, Valerie Popp, Michael Power, Kathrin Groeneveld, Jie Yan, Christian Melle, Luke E. Rogerson, Marlly Achury, Frank Schwede, Torsten Straßer, Thomas Euler, François Paquet‐Durand, Vasilica Nache
Abstract
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.