Do calcium channel blockers rescue dying photoreceptors in the Pde6b ( rd1 ) mouse?
Retinitis pigmentosa (RP) is a genetically heterogeneous set of blinding diseases that affects more than a million people worldwide. In humans, ~5-8% of recessive and dominant RP cases are caused by nonsense mutations in the Pde6b gene coding for the ss-subunit of the rod photoreceptor cGMP phosphodiesterase 6 (PDE6-ss). The study of the disease has been greatly aided by the Pde6b ( rd1 ) (rd1) mouse model of RP carrying a null PDE6ss allele. Degenerating rd1 rods were found to experience a pathological increase in intracellular calcium concentration ('Ca overload') when they enter the apoptotic process at postnatal day 10. A 1999 study suggested that the Ca(2+) channel antagonist D-cis diltiazem delays the kinetics of rd1 rod degeneration, conferring partial rescue of scotopic vision. Subsequent reports were mixed: whereas several studies failed to replicate the original results, others appeared to confirm the neuroprotective effects of Ca(2+) channel antagonists such as diltiazem, nilvadipine and verapamil. We discuss the discrepancies between the results of different groups and suggest plausible causes for the discordant results. We also discuss potential involvement of recently identified Ca(2+)-dependent mechanisms that include protective calcium ATPase mechanisms, ryanodine and IP3 calcium stores, and store operated channels in Pde6b ( rd1 ) neurodegeneration.
Department of Ophthalmology and Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Peter
P
Barabas
Carolee
C
Cutler Peck
David
D
Krizaj
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000172:deficiency* / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D004195:Disease Models, Animal; D051379:Mice; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects* / Q000473:pathology*
D002121:Calcium Channel Blockers; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6