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Melanopsin mediates light-dependent relaxation in blood vessels
Contributed by Solomon H. Snyder, October 24, 2014 (sent for review June 22, 2014)

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.
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.
Footnotes
- ↵1To whom correspondence may be addressed. Email: ssnyder{at}jhmi.edu or dberkow1{at}jhmi.edu.
Author contributions: G.S., D.P., J.S., V.B., L.S., D.N., M.K.H., R.C.K., S.H.S., L.A.S., and D.E.B. designed research; G.S., G.P.H., D.P., S.C., D.H., J.T.P., J.S., J.H.K., A.C.M., L.S., M.K.H., L.A.S., and D.E.B. performed research; D.P., L.S., L.A.S., and D.E.B. contributed new reagents/analytic tools; G.S., G.P.H., S.C., D.H., J.T.P., J.S., J.H.K., V.B., A.C.M., M.K.H., R.C.K., S.H.S., L.A.S., and D.E.B. analyzed data; and G.S., D.N., R.C.K., S.H.S., L.A.S., and D.E.B. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1420258111/-/DCSupplemental.
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