Journal Article

Melanopsin mediates light-dependent relaxation in blood vessels

Santhanam, Lakshmi, Park, Jong Taek, Sikka, Gautam, Koehler, Raymond C., Snyder, Solomon H., Myers, Allen C., Nyhan, Daniel, Hussmann, G. Patrick, Barodka, Viachaslau, Halushka, Marc K., Hori, Daijiro, Berkowitz, Dan E., Pandey, Deepesh, Cao, Suyi, Kim, Jae Hyung, Steppan, Jochen, Shimoda, Larissa A.

2014

Overview

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. Significance Non–image-forming opsins such as Opn4 regulate important physiological functions such as circadian photo-entrainment and affect. The recent discovery that melanopsin (Opn4) functions outside the central nervous system prompted us to explore a potential role for this receptor in blood vessel regulation. We hypothesized that Opn4-mediated signaling might explain the phenomenon of photorelaxation, for which a mechanism has remained elusive. We report the presence in blood vessels of Opn4 and demonstrate that it mediates wavelength-specific, light-dependent vascular relaxation. This photorelaxation signal transduction involves cGMP and phosphodiesterase 6, but not protein kinase G. Furthermore it is regulated by G protein-coupled receptor kinase 2 and involves vascular hyperpolarization. This receptor pathway can be harnessed for wavelength-specific light-based therapy in the treatment of diseases that involve altered vasoreactivity.

• Publisher: National Academy of Sciences
• Subject: Animals / Aorta / Biological Sciences / Blood vessels / Blood Vessels - metabolism / Blood Vessels - physiology / Blotting, Western / Carbon monoxide / Cells / central nervous system / cGMP-dependent protein kinase / cyclic GMP / Cyclic GMP - metabolism / Cyclic Nucleotide Phosphodiesterases, Type 6 - metabolism / G-protein coupled receptors / G-Protein-Coupled Receptor Kinase 2 - metabolism / Gene expression / Glycoproteins / Kinases / Laser-Doppler Flowmetry / Light / Medical Sciences / Mice / Myography / Nitric oxide / opsin / Opsins / Photoreceptors / Physiological regulation / Physiology / Receptors / Reverse Transcriptase Polymerase Chain Reaction / Rod Opsins - metabolism / Signal transduction / Signal Transduction - physiology / Smooth muscle / therapeutics / Vasodilation / Vasodilation - physiology / Vasodilation - radiation effects / Wavelengths