title: An intersubunit interaction regulates trafficking of rod cyclic nucleotide-gated channels and is disrupted in an inherited form of blindness.
abstract: A mutation in a cyclic nucleotide-gated channel (CNGA1) is associated with retinitis pigmentosa (RP), a common, inherited eye disease. Expression of mutant (CNGA1-RP) homomeric channels in Xenopus oocytes revealed no measurable differences compared to wild-type CNGA1 homomers. As native retinal rod CNG channels comprise CNGA1 and CNGB1 subunits, we coexpressed CNGA1-RP and CNGB1. Surprisingly, this subunit combination did not produce detectable channels at the membrane surface. We show that the mechanism underlying this defect involves an intersubunit interaction between CNGA1 and CNGB1 that was not formed between CNGA1-RP and CNGB1 subunits. In the absence of this interaction, a short N-terminal region in CNGB1 prevented membrane expression. Thus, disruption of a regulatory interaction by mutation in CNGA1 exposed a region of CNGB1 that disrupted surface expression of heteromeric CNGA1-RP/CNGB1 channels, accounting for this instance of RP.
authors.affiliation: Department of Physiology and Biophysics, Howard Hughes Medical Institute, University of Washington Medical School, Seattle, WA 98195, USA.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Trudeau
authors.forename: William N
authors.initials: WN
authors.lastname: Zagotta
mesh_terms: D000818:Animals; D001766:Blindness / Q000235:genetics* / Q000378:metabolism*; D002417:Cattle; D054815:Cyclic Nucleotide-Gated Cation Channels; D005260:Female; D017353:Gene Deletion; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D009154:Mutation / Q000502:physiology; D009712:Nucleotides, Cyclic / Q000378:metabolism*; D009865:Oocytes; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism*; D012174:Retinitis Pigmentosa / Q000235:genetics; D014982:Xenopus laevis
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D007473:Ion Channels; D009712:Nucleotides, Cyclic