Redefining the role of Ca 2+ -permeable channels in photoreceptor degeneration using diltiazem

• Published in: Cell death & disease Vol. 13; no. 1; p. 47
• Main Authors: Das, Soumyaparna, Popp, Valerie, Power, Michael, Groeneveld, Kathrin, Yan, Jie, Melle, Christian, Rogerson, Luke, Achury, Marlly, Schwede, Frank, Strasser, Torsten, Euler, Thomas, Paquet-Durand, François, Nache, Vasilica
• Format: Journal Article
• Language: English
• Published: England 10.01.2022
• Subjects: Animals; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Calcium Channels - metabolism; Cell Death - drug effects; Cyclic GMP - metabolism; Cyclic Nucleotide-Gated Cation Channels - metabolism; Diltiazem - chemistry; Diltiazem - pharmacology; Ion Channel Gating - drug effects; Kinetics; Mice; Proteolysis; Retinal Cone Photoreceptor Cells - drug effects; Retinal Cone Photoreceptor Cells - metabolism; Retinal Cone Photoreceptor Cells - pathology; Retinal Degeneration - metabolism; Retinal Degeneration - pathology; Retinal Rod Photoreceptor Cells - drug effects; Retinal Rod Photoreceptor Cells - metabolism; Retinal Rod Photoreceptor Cells - pathology
• ISSN: 2041-4889

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