title: CNG-modulin: a novel Ca-dependent modulator of ligand sensitivity in cone photoreceptor cGMP-gated ion channels.
abstract: The transduction current in several different types of sensory neurons arises from the activity of cyclic nucleotide-gated (CNG) ion channels. The channels in these sensory neurons vary in structure and function, yet each one demonstrates calcium-dependent modulation of ligand sensitivity mediated by the interaction of the channel with a soluble modulator protein. In cone photoreceptors, the molecular identity of the modulator protein was previously unknown. We report the discovery and characterization of CNG-modulin, a novel 301 aa protein that interacts with the N terminus of the β subunit of the cGMP-gated channel and modulates the cGMP sensitivity of the channels in cone photoreceptors of striped bass (Morone saxatilis). Immunohistochemistry and single-cell PCR demonstrate that CNG-modulin is expressed in cone but not rod photoreceptors. Adding purified recombinant CNG-modulin to cone membrane patches containing the native CNG channels shifts the midpoint of cGMP dependence from ∼91 μM in the absence of Ca(2+) to ∼332 μM in the presence of 20 μM Ca(2+). At a fixed cGMP concentration, the midpoint of the Ca(2+) dependence is ∼857 nM Ca(2+). These restored physiological features are statistically indistinguishable from the effects of the endogenous modulator. CNG-modulin binds Ca(2+) with a concentration dependence that matches the calcium dependence of channel modulation. We conclude that CNG-modulin is the authentic Ca(2+)-dependent modulator of cone CNG channel ligand sensitivity. CNG-modulin is expressed in other tissues, such as brain, olfactory epithelium, and the inner ear, and may modulate the function of ion channels in those tissues as well.
authors.affiliation: Department of Physiology, School of Medicine, University of California at San Francisco, San Francisco, California 94143, USA. tatiana.rebrik@duke.edu
authors.forename: Tatiana I
authors.initials: TI
authors.lastname: Rebrik
authors.forename: Inna
authors.initials: I
authors.lastname: Botchkina
authors.forename: Vadim Y
authors.initials: VY
authors.lastname: Arshavsky
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Craft
authors.forename: Juan I
authors.initials: JI
authors.lastname: Korenbrot
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001492:Bass; D002118:Calcium / Q000502:physiology*; D006152:Cyclic GMP / Q000378:metabolism* / Q000502:physiology; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000378:metabolism* / Q000502:physiology; D015640:Ion Channel Gating / Q000502:physiology*; D008024:Ligands; D008969:Molecular Sequence Data; D051603:Recoverin / Q000502:physiology*; D017949:Retinal Cone Photoreceptor Cells / Q000502:physiology*
chemical_list: D054815:Cyclic Nucleotide-Gated Cation Channels; D008024:Ligands; D051603:Recoverin; D006152:Cyclic GMP; D002118:Calcium