Retinoids restore normal cyclic nucleotide sensitivity of mutantion channels associated with cone dystrophy

[摘要] Purpose: To determine whether inhibition of cyclic nucleotide-gated(CNG) ion channels by retinoids might be useful in treating degenerativeretinal diseases in which either the CNG channels are hypersensitive to3',5'-cyclic guanosine monophosphate (cGMP) or the photoreceptor cGMPconcentration is elevated.Methods: Patch clamp (electrophysiological) methods were used tomeasure activation by cGMP of wild-type human cone (hCNGA3), mutant cone(hCNGA3-N471S), and wild-type bovine rod (bCNGA1) CNG channelsheterologously expressed in Xenopus oocytes. Cyclic GMP-activatedcurrents were measured in excised, inside-out membrane patches beforeand after treatment with either all-trans retinal (ATR) orall-trans C22 aldehyde, which is too long to fit into thechromophore binding pocket of opsin and therefore cannot activate thevisual transduction cascade.Results: At physiological cGMP concentrations, 150 nM ATR reducedthe open probability of the mutant cone CNG channel by reducing itsapparent cGMP affinity to that of the normal cone channel. Furthermore,all-trans C22 aldehyde similarly inhibited the mutant cone channelas well as normal rod and cone CNG channels.Conclusions: Our results raise the possibility that retinoids, suchas all-trans C22 aldehyde, that inhibit CNG channels withoutaffecting the transduction cascade, may be useful in treatingdegenerative retinal diseases in which either the cGMP concentration iselevated or the CNG channels are hypersensitive to cGMP.

[学科分类] 生物化学/生物物理