Retinoids restore normal cyclic nucleotide sensitivity of mutant ion channels associated with cone dystrophy.
OBJECTIVE
To determine whether inhibition of cyclic nucleotide-gated (CNG) ion channels by retinoids might be useful in treating degenerative retinal diseases in which either the CNG channels are hypersensitive to 3',5'-cyclic guanosine monophosphate (cGMP) or the photoreceptor cGMP concentration is elevated.


METHODS
Patch clamp (electrophysiological) methods were used to measure activation by cGMP of wild-type human cone (hCNGA3), mutant cone (hCNGA3-N471S), and wild-type bovine rod (bCNGA1) CNG channels heterologously expressed in Xenopus oocytes. Cyclic GMP-activated currents were measured in excised, inside-out membrane patches before and after treatment with either all-trans retinal (ATR) or all-trans C22 aldehyde, which is too long to fit into the chromophore binding pocket of opsin and therefore cannot activate the visual transduction cascade.


RESULTS
At physiological cGMP concentrations, 150 nM ATR reduced the open probability of the mutant cone CNG channel by reducing its apparent cGMP affinity to that of the normal cone channel. Furthermore, all-trans C22 aldehyde similarly inhibited the mutant cone channel as well as normal rod and cone CNG channels.


CONCLUSIONS
Our results raise the possibility that retinoids, such as all-trans C22 aldehyde, that inhibit CNG channels without affecting the transduction cascade, may be useful in treating degenerative retinal diseases in which either the cGMP concentration is elevated or the CNG channels are hypersensitive to cGMP.
Tetreault
Michelle L
ML
Department of Molecular Pharmacology, Physiology & Biotechnology Brown Medical School, Providence, RI 02912, USA.
Horrigan
Diana M
DM
Kim
Jennifer A
JA
Zimmerman
Anita L
AL
D000818:Animals; D001216:Asparagine; D002417:Cattle; D006152:Cyclic GMP / Q000494:pharmacology*; D054815:Cyclic Nucleotide-Gated Cation Channels; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D009865:Oocytes; D018408:Patch-Clamp Techniques; D012174:Retinitis Pigmentosa / Q000188:drug therapy / Q000235:genetics*; D012176:Retinoids / Q000494:pharmacology*; D012694:Serine; D014161:Transduction, Genetic; D014801:Vitamin A / Q000494:pharmacology; D014981:Xenopus
C516781:C22 aldehyde; C475741:CNGA1 protein, bovine; D054815:Cyclic Nucleotide-Gated Cation Channels; D007473:Ion Channels; D012176:Retinoids; D014801:Vitamin A; D012694:Serine; D001216:Asparagine; D006152:Cyclic GMP