title: Melanopsin mediates light-dependent relaxation in blood vessels.
abstract: Melanopsin (opsin4; Opn4), a non-image-forming opsin, has been linked to a number of behavioral responses to light, including circadian photo-entrainment, light suppression of activity in nocturnal animals, and alertness in diurnal animals. We report a physiological role for Opn4 in regulating blood vessel function, particularly in the context of photorelaxation. Using PCR, we demonstrate that Opn4 (a classic G protein-coupled receptor) is expressed in blood vessels. Force-tension myography demonstrates that vessels from Opn4(-/-) mice fail to display photorelaxation, which is also inhibited by an Opn4-specific small-molecule inhibitor. The vasorelaxation is wavelength-specific, with a maximal response at ∼430-460 nm. Photorelaxation does not involve endothelial-, nitric oxide-, carbon monoxide-, or cytochrome p450-derived vasoactive prostanoid signaling but is associated with vascular hyperpolarization, as shown by intracellular membrane potential measurements. Signaling is both soluble guanylyl cyclase- and phosphodiesterase 6-dependent but protein kinase G-independent. β-Adrenergic receptor kinase 1 (βARK 1 or GRK2) mediates desensitization of photorelaxation, which is greatly reduced by GRK2 inhibitors. Blue light (455 nM) regulates tail artery vasoreactivity ex vivo and tail blood blood flow in vivo, supporting a potential physiological role for this signaling system. This endogenous opsin-mediated, light-activated molecular switch for vasorelaxation might be harnessed for therapy in diseases in which altered vasoreactivity is a significant pathophysiologic contributor.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
authors.forename: Gautam
authors.initials: G
authors.lastname: Sikka
authors.affiliation: Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205;
authors.forename: G Patrick
authors.initials: GP
authors.lastname: Hussmann
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
authors.forename: Deepesh
authors.initials: D
authors.lastname: Pandey
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
authors.forename: Suyi
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Surgery, Johns Hopkins University, Baltimore, MD 21287;
authors.forename: Daijiro
authors.initials: D
authors.lastname: Hori
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
authors.forename: Jong Taek
authors.initials: JT
authors.lastname: Park
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
authors.forename: Jochen
authors.initials: J
authors.lastname: Steppan
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
authors.forename: Jae Hyung
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
authors.forename: Viachaslau
authors.initials: V
authors.lastname: Barodka
authors.affiliation: Department of Allergy and Immunology, Johns Hopkins University, Baltimore, MD 21224;
authors.forename: Allen C
authors.initials: AC
authors.lastname: Myers
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205;
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Santhanam
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
authors.forename: Daniel
authors.initials: D
authors.lastname: Nyhan
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD 21287; and.
authors.forename: Marc K
authors.initials: MK
authors.lastname: Halushka
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Koehler
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, MD 21287; and ssnyder@jhmi.edu dberkow1@jhmi.edu.
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
authors.affiliation: Division of Pulmonary Medicine, Johns Hopkins University, Baltimore, MD 21224.
authors.forename: Larissa A
authors.initials: LA
authors.lastname: Shimoda
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287; Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205; ssnyder@jhmi.edu dberkow1@jhmi.edu.
authors.forename: Dan E
authors.initials: DE
authors.lastname: Berkowitz
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000378:metabolism / Q000502:physiology*; D015153:Blotting, Western; D006152:Cyclic GMP / Q000378:metabolism; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000378:metabolism; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism; D017078:Laser-Doppler Flowmetry; D008027:Light; D051379:Mice; D009213:Myography; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017299:Rod Opsins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology* / Q000528:radiation effects; D000099210:Melanopsin
chemical_list: D006152:Cyclic GMP; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D054769:G-Protein-Coupled Receptor Kinase 2; D017299:Rod Opsins; D000099210:Melanopsin; C496568:GRK2 protein, mouse
keywords: GRK2; melanopsin; opsin; photorelaxation; signal transduction