Redefining the role of Ca2+-permeable channels in hereditary photoreceptor degeneration using the D- and L-cis enantiomers of diltiazem

Das, S.; Popp, V.; Power, M. J.; Groeneveld, K.; Melle, C.; Rogerson, L. E.; Achury, M. N.; Schwede, F.; Strasser, T.; Euler, T.; Paquet-Durand, F.; Nache, V.

doi:10.1101/2020.12.04.411827

bioRxiv · 10.1101/2020.12.04.411827

Redefining the role of Ca2+-permeable channels in hereditary photoreceptor degeneration using the D- and L-cis enantiomers of diltiazem

Das, S.·Popp, V.·Power, M. J.·Groeneveld, K.·Melle, C.·Rogerson, L. E.·Achury, M. N.·Schwede, F.·Strasser, T.·Euler, T.·Paquet-Durand, F.·Nache, V.

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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.

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Das, S., Popp, V., Power, M. J., Groeneveld, K., Melle, C., Rogerson, L. E., Achury, M. N., Schwede, F., Strasser, T., Euler, T., Paquet-Durand, F., Nache, V.. 2020-12-06. Redefining the role of Ca2+-permeable channels in hereditary photoreceptor degeneration using the D- and L-cis enantiomers of diltiazem. https://doi.org/10.1101/2020.12.04.411827

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