Opsin 3 and 4 mediate light-induced pulmonary vasorelaxation that is potentiated by G protein-coupled receptor kinase 2 inhibition

Sebastian Barreto Ortiz, Daijiro Hori, Yohei Nomura, Xin Yun, Haiyang Jiang, Hwanmee Yong, James Chen, Sam Paek, Deepesh Pandey, Gautam Sikka, Anil Bhatta, Andrew Gillard, Jochen Steppan, Jae Hyung Kim, Hideo Adachi, Viachaslau Barodka, Lewis Romer, Steven An, Larissa Shimoda, Lakshmi SanthanamDan E Berkowitz

Research output: Contribution to journalArticle

Abstract

We recently demonstrated that blue light induces vasorelaxation in the systemic mouse circulation, a phenomenon mediated by the nonvisual G protein-coupled receptor melanopsin (Opsin 4; Opn4). Here we tested the hypothesis that nonvisual opsins mediate photorelaxation in the pulmonary circulation. We discovered Opsin 3 (Opn3), Opn4, and G protein-coupled receptor kinase 2 (GRK2) in rat pulmonary arteries (PAs) and in pulmonary arterial smooth muscle cells (PASMCs), where the opsins interact directly with GRK2, as demonstrated with a proximity ligation assay. Light elicited an intensity-dependent relaxation of PAs preconstricted with phenylephrine (PE), with a maximum response between 400 and 460 nm (blue light). Wavelength-specific photorelaxation was attenuated in PAs from Opn4-/- mice and further reduced following shRNA-mediated knockdown of Opn3. Inhibition of GRK2 amplified the response and prevented physiological desensitization to repeated light exposure. Blue light also prevented PE-induced constriction in isolated PAs, decreased basal tone, ablated PE-induced single-cell contraction of PASMCs, and reversed PE-induced depolarization in PASMCs when GRK2 was inhibited. The photorelaxation response was modulated by soluble guanylyl cyclase but not by protein kinase G or nitric oxide. Most importantly, blue light induced significant vasorelaxation of PAs from rats with chronic pulmonary hypertension and effectively lowered pulmonary arterial pressure in isolated intact perfused rat lungs subjected to acute hypoxia. These findings show that functional Opn3 and Opn4 in PAs represent an endogenous “optogenetic system” that mediates photorelaxation in the pulmonary vasculature. Phototherapy in conjunction with GRK2 inhibition could therefore provide an alternative treatment strategy for pulmonary vasoconstrictive disorders.

Original languageEnglish (US)
Pages (from-to)L93-L106
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume314
Issue number1
DOIs
StatePublished - Jan 1 2018

Fingerprint

G-Protein-Coupled Receptor Kinase 2
Opsins
Vasodilation
Pulmonary Artery
Light
Lung
Phenylephrine
Smooth Muscle Myocytes
Optogenetics
Cyclic GMP-Dependent Protein Kinases
Pulmonary Circulation
Phototherapy
G-Protein-Coupled Receptors
Pulmonary Hypertension
Constriction
Small Interfering RNA
Ligation
Arterial Pressure
Nitric Oxide

Keywords

  • GRK2
  • Opsins
  • Photorelaxation
  • Pulmonary artery smooth muscle
  • Pulmonary hypertension

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Opsin 3 and 4 mediate light-induced pulmonary vasorelaxation that is potentiated by G protein-coupled receptor kinase 2 inhibition. / Barreto Ortiz, Sebastian; Hori, Daijiro; Nomura, Yohei; Yun, Xin; Jiang, Haiyang; Yong, Hwanmee; Chen, James; Paek, Sam; Pandey, Deepesh; Sikka, Gautam; Bhatta, Anil; Gillard, Andrew; Steppan, Jochen; Kim, Jae Hyung; Adachi, Hideo; Barodka, Viachaslau; Romer, Lewis; An, Steven; Shimoda, Larissa; Santhanam, Lakshmi; Berkowitz, Dan E.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 314, No. 1, 01.01.2018, p. L93-L106.

Research output: Contribution to journalArticle

Barreto Ortiz, Sebastian ; Hori, Daijiro ; Nomura, Yohei ; Yun, Xin ; Jiang, Haiyang ; Yong, Hwanmee ; Chen, James ; Paek, Sam ; Pandey, Deepesh ; Sikka, Gautam ; Bhatta, Anil ; Gillard, Andrew ; Steppan, Jochen ; Kim, Jae Hyung ; Adachi, Hideo ; Barodka, Viachaslau ; Romer, Lewis ; An, Steven ; Shimoda, Larissa ; Santhanam, Lakshmi ; Berkowitz, Dan E. / Opsin 3 and 4 mediate light-induced pulmonary vasorelaxation that is potentiated by G protein-coupled receptor kinase 2 inhibition. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2018 ; Vol. 314, No. 1. pp. L93-L106.
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abstract = "We recently demonstrated that blue light induces vasorelaxation in the systemic mouse circulation, a phenomenon mediated by the nonvisual G protein-coupled receptor melanopsin (Opsin 4; Opn4). Here we tested the hypothesis that nonvisual opsins mediate photorelaxation in the pulmonary circulation. We discovered Opsin 3 (Opn3), Opn4, and G protein-coupled receptor kinase 2 (GRK2) in rat pulmonary arteries (PAs) and in pulmonary arterial smooth muscle cells (PASMCs), where the opsins interact directly with GRK2, as demonstrated with a proximity ligation assay. Light elicited an intensity-dependent relaxation of PAs preconstricted with phenylephrine (PE), with a maximum response between 400 and 460 nm (blue light). Wavelength-specific photorelaxation was attenuated in PAs from Opn4-/- mice and further reduced following shRNA-mediated knockdown of Opn3. Inhibition of GRK2 amplified the response and prevented physiological desensitization to repeated light exposure. Blue light also prevented PE-induced constriction in isolated PAs, decreased basal tone, ablated PE-induced single-cell contraction of PASMCs, and reversed PE-induced depolarization in PASMCs when GRK2 was inhibited. The photorelaxation response was modulated by soluble guanylyl cyclase but not by protein kinase G or nitric oxide. Most importantly, blue light induced significant vasorelaxation of PAs from rats with chronic pulmonary hypertension and effectively lowered pulmonary arterial pressure in isolated intact perfused rat lungs subjected to acute hypoxia. These findings show that functional Opn3 and Opn4 in PAs represent an endogenous “optogenetic system” that mediates photorelaxation in the pulmonary vasculature. Phototherapy in conjunction with GRK2 inhibition could therefore provide an alternative treatment strategy for pulmonary vasoconstrictive disorders.",
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T1 - Opsin 3 and 4 mediate light-induced pulmonary vasorelaxation that is potentiated by G protein-coupled receptor kinase 2 inhibition

AU - Barreto Ortiz, Sebastian

AU - Hori, Daijiro

AU - Nomura, Yohei

AU - Yun, Xin

AU - Jiang, Haiyang

AU - Yong, Hwanmee

AU - Chen, James

AU - Paek, Sam

AU - Pandey, Deepesh

AU - Sikka, Gautam

AU - Bhatta, Anil

AU - Gillard, Andrew

AU - Steppan, Jochen

AU - Kim, Jae Hyung

AU - Adachi, Hideo

AU - Barodka, Viachaslau

AU - Romer, Lewis

AU - An, Steven

AU - Shimoda, Larissa

AU - Santhanam, Lakshmi

AU - Berkowitz, Dan E

PY - 2018/1/1

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N2 - We recently demonstrated that blue light induces vasorelaxation in the systemic mouse circulation, a phenomenon mediated by the nonvisual G protein-coupled receptor melanopsin (Opsin 4; Opn4). Here we tested the hypothesis that nonvisual opsins mediate photorelaxation in the pulmonary circulation. We discovered Opsin 3 (Opn3), Opn4, and G protein-coupled receptor kinase 2 (GRK2) in rat pulmonary arteries (PAs) and in pulmonary arterial smooth muscle cells (PASMCs), where the opsins interact directly with GRK2, as demonstrated with a proximity ligation assay. Light elicited an intensity-dependent relaxation of PAs preconstricted with phenylephrine (PE), with a maximum response between 400 and 460 nm (blue light). Wavelength-specific photorelaxation was attenuated in PAs from Opn4-/- mice and further reduced following shRNA-mediated knockdown of Opn3. Inhibition of GRK2 amplified the response and prevented physiological desensitization to repeated light exposure. Blue light also prevented PE-induced constriction in isolated PAs, decreased basal tone, ablated PE-induced single-cell contraction of PASMCs, and reversed PE-induced depolarization in PASMCs when GRK2 was inhibited. The photorelaxation response was modulated by soluble guanylyl cyclase but not by protein kinase G or nitric oxide. Most importantly, blue light induced significant vasorelaxation of PAs from rats with chronic pulmonary hypertension and effectively lowered pulmonary arterial pressure in isolated intact perfused rat lungs subjected to acute hypoxia. These findings show that functional Opn3 and Opn4 in PAs represent an endogenous “optogenetic system” that mediates photorelaxation in the pulmonary vasculature. Phototherapy in conjunction with GRK2 inhibition could therefore provide an alternative treatment strategy for pulmonary vasoconstrictive disorders.

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