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

• DOI: 10.1038/s41419-021-04482-1
• Publication Date: 2022-01-10T12:04:21Z
• Authors: Soumyaparna Das; Valerie Popp; Michael Power; Kathrin Groeneveld; Jie Yan; Christian Melle; Luke Rogerson; Marlly Achury; Frank Schwede; Torsten Strasser; Thomas Euler; François Paquet-D...; Vasilica Nache
• Keywords: 0301 basic medicine; QH573-671; Cell Death; Retinal Degeneration; Cyclic Nucleotide-Gated Cation Channels; Calcium Channel Blockers; Article; Diltiazem; Kinetics; Mice; 03 medical and health sciences; Retinal Rod Photoreceptor Cells; Proteolysis; Retinal Cone Photoreceptor Cells; Animals; Calcium; Calcium Channels; Cytology; Cyclic GMP; Ion Channel Gating

AbstractHereditary 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.