title: Bicarbonate Modulates Photoreceptor Guanylate Cyclase (ROS-GC) Catalytic Activity.
abstract: By generating the second messenger cGMP in retinal rods and cones, ROS-GC plays a central role in visual transduction. Guanylate cyclase-activating proteins (GCAPs) link cGMP synthesis to the light-induced fall in [Ca(2+)]i to help set absolute sensitivity and assure prompt recovery of the response to light. The present report discloses a surprising feature of this system: ROS-GC is a sensor of bicarbonate. Recombinant ROS-GCs synthesized cGMP from GTP at faster rates in the presence of bicarbonate with an ED50 of 27 mM for ROS-GC1 and 39 mM for ROS-GC2. The effect required neither Ca(2+) nor use of the GCAPs domains; however, stimulation of ROS-GC1 was more powerful in the presence of GCAP1 or GCAP2 at low [Ca(2+)]. When applied to retinal photoreceptors, bicarbonate enhanced the circulating current, decreased sensitivity to flashes, and accelerated flash response kinetics. Bicarbonate was effective when applied either to the outer or inner segment of red-sensitive cones. In contrast, bicarbonate exerted an effect when applied to the inner segment of rods but had little efficacy when applied to the outer segment. The findings define a new regulatory mechanism of the ROS-GC system that affects visual transduction and is likely to affect the course of retinal diseases caused by cGMP toxicity.
authors.affiliation: From the Research Divisions of Biochemistry and Molecular Biology, Unit of Regulatory and Molecular Biology, Salus University, Elkins Park, Pennsylvania 19027 and.
authors.forename: Teresa
authors.initials: T
authors.lastname: Duda
authors.affiliation: the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Wen
authors.affiliation: the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Tomoki
authors.initials: T
authors.lastname: Isayama
authors.affiliation: From the Research Divisions of Biochemistry and Molecular Biology, Unit of Regulatory and Molecular Biology, Salus University, Elkins Park, Pennsylvania 19027 and.
authors.forename: Rameshwar K
authors.initials: RK
authors.lastname: Sharma
authors.affiliation: the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114 cmakino@meei.harvard.edu.
authors.forename: Clint L
authors.initials: CL
authors.lastname: Makino
mesh_terms: D000818:Animals; D001639:Bicarbonates / Q000633:toxicity*; D019556:COS Cells; D020013:Calcium Signaling / Q000187:drug effects*; D002384:Catalysis; D002417:Cattle; D002522:Chlorocebus aethiops; D006152:Cyclic GMP / Q000235:genetics / Q000378:metabolism; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D001639:Bicarbonates; D006162:Guanylate Cyclase; D006152:Cyclic GMP
keywords: Bicarbonate; Cilia; Cyclic GMP (cGMP); Guanylate Cyclase (Guanylyl Cyclase); Neuroscience; Photoreceptor; Photoreceptor ROS-GC; Phototransduction; Receptor Regulation; Signal Transduction