shRNA knockdown of guanylate cyclase 2e or cyclic nucleotide gated channel alpha 1 increases photoreceptor survival in a cGMP phosphodiesterase …

J Tosi, RJ Davis, NK Wang, M Naumann… - Journal of cellular …, 2011 - Wiley Online Library
J Tosi, RJ Davis, NK Wang, M Naumann, CS Lin, SH Tsang
Journal of cellular and molecular medicine, 2011Wiley Online Library
In vertebrate rods, dark and light conditions produce changes in guanosine 3′, 5′‐cyclic
monophosphate (cGMP) and calcium (Ca2+) levels, which are regulated by the opposing
function of several proteins. During the recovery of a bright flash, guanylate cyclase (GUCY)
helps raise cGMP to levels that open cGMP‐gated calcium sodium channels (CNG) to
increase Na+ and Ca2+ influx in the outer segment. In contrast, light activates cGMP
phosphodiesterase 6 (PDE6) causing rapid hydrolysis of cGMP, CNG closure, and reduced …
Abstract
In vertebrate rods, dark and light conditions produce changes in guanosine 3′,5′‐cyclic monophosphate (cGMP) and calcium (Ca2+) levels, which are regulated by the opposing function of several proteins. During the recovery of a bright flash, guanylate cyclase (GUCY) helps raise cGMP to levels that open cGMP‐gated calcium sodium channels (CNG) to increase Na+ and Ca2+ influx in the outer segment. In contrast, light activates cGMP phosphodiesterase 6 (PDE6) causing rapid hydrolysis of cGMP, CNG closure, and reduced Na+ and Ca2+ levels. In Pde6b mouse models of retinitis pigmentosa (RP), photoreceptor death is preceded by abnormally high cGMP and Ca2+ levels, likely because of continued synthesis of cGMP by guanylate cyclases and unregulated influx of Ca2+ to toxic levels through CNG channels. To reverse the effects of Pde6b loss of function, we employed an shRNA knockdown approach to reduce the expression of Gucy2e or Cnga1 in Pde6bH620Q photoreceptors prior to degeneration. Gucy2e‐ or Cnga1‐shRNA lentiviral‐mediated knockdown GUCY2E and CNGA1 expression increase visual function and photoreceptor survival in Pde6bH620Q mice. We demonstrated that effective knockdown of GUCY2E and CNGA1 expression to counteract loss of PDE6 function may develop into a valuable approach for treating some patients with RP.
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