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Research Article

Melanopsin mediates light-dependent relaxation in blood vessels

Gautam Sikka, G. Patrick Hussmann, Deepesh Pandey, Suyi Cao, Daijiro Hori, Jong Taek Park, Jochen Steppan, Jae Hyung Kim, Viachaslau Barodka, Allen C. Myers, Lakshmi Santhanam, Daniel Nyhan, Marc K. Halushka, Raymond C. Koehler, Solomon H. Snyder, Larissa A. Shimoda, and Dan E. Berkowitz
PNAS first published November 17, 2014; https://doi.org/10.1073/pnas.1420258111
Gautam Sikka
aDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
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G. Patrick Hussmann
bDepartment of Neuroscience, Johns Hopkins University, Baltimore, MD 21205;
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Deepesh Pandey
aDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
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Suyi Cao
aDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
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Daijiro Hori
cDepartment of Surgery, Johns Hopkins University, Baltimore, MD 21287;
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Jong Taek Park
aDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
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Jochen Steppan
aDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
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Jae Hyung Kim
aDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
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Viachaslau Barodka
aDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
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Allen C. Myers
dDepartment of Allergy and Immunology, Johns Hopkins University, Baltimore, MD 21224;
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Lakshmi Santhanam
aDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
eDepartment of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205;
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Daniel Nyhan
aDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
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Marc K. Halushka
fDepartment of Pathology, Johns Hopkins University, Baltimore, MD 21287; and
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Raymond C. Koehler
aDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
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Solomon H. Snyder
fDepartment of Pathology, Johns Hopkins University, Baltimore, MD 21287; and
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  • For correspondence: ssnyder@jhmi.edu dberkow1@jhmi.edu
Larissa A. Shimoda
gDivision of Pulmonary Medicine, Johns Hopkins University, Baltimore, MD 21224
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Dan E. Berkowitz
aDepartment of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD 21287;
eDepartment of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205;
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  • For correspondence: ssnyder@jhmi.edu dberkow1@jhmi.edu
  1. Contributed by Solomon H. Snyder, October 24, 2014 (sent for review June 22, 2014)

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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.

  • photorelaxation
  • opsin
  • melanopsin
  • signal transduction
  • GRK2

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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Melanopsin-mediated vasorelaxation
Gautam Sikka, G. Patrick Hussmann, Deepesh Pandey, Suyi Cao, Daijiro Hori, Jong Taek Park, Jochen Steppan, Jae Hyung Kim, Viachaslau Barodka, Allen C. Myers, Lakshmi Santhanam, Daniel Nyhan, Marc K. Halushka, Raymond C. Koehler, Solomon H. Snyder, Larissa A. Shimoda, Dan E. Berkowitz
Proceedings of the National Academy of Sciences Nov 2014, 201420258; DOI: 10.1073/pnas.1420258111

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Melanopsin-mediated vasorelaxation
Gautam Sikka, G. Patrick Hussmann, Deepesh Pandey, Suyi Cao, Daijiro Hori, Jong Taek Park, Jochen Steppan, Jae Hyung Kim, Viachaslau Barodka, Allen C. Myers, Lakshmi Santhanam, Daniel Nyhan, Marc K. Halushka, Raymond C. Koehler, Solomon H. Snyder, Larissa A. Shimoda, Dan E. Berkowitz
Proceedings of the National Academy of Sciences Nov 2014, 201420258; DOI: 10.1073/pnas.1420258111
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