Control of coronary vascular resistance by eicosanoids via a novel GPCR

Sanjiv Kaul, Anthony P. Barnes, Nabil J. Alkayed, Zhiping Cao, Zu Yuan Qian, Shanthi Nagarajan, Xuehong Liu, Jonathan W. Nelson, Fuchun Xie, Bingbing Li, Wei Fan, Lijuan Liu, Marjorie R. Grafe, Xiangshu Xiao, Catherine M. Davis

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Arachidonic acid metabolites epoxyeicosatrienoates (EETs) and hydroxyeicosatetraenoates (HETEs) are important regulators of myocardial blood flow and coronary vascular resistance (CVR), but their mechanisms of action are not fully understood. We applied a chemoproteomics strategy using a clickable photoaffinity probe to identify G protein-coupled receptor 39 (GPR39) as a microvascular smooth muscle cell (mVSMC) receptor selective for two endogenous eicosanoids, 15-HETE and 14,15-EET, which act on the receptor to oppose each other’s activity. The former increases mVSMC intracellular calcium via GPR39 and augments coronary microvascular resistance, and the latter inhibits these actions. Furthermore, we find that the efficacy of both ligands is potentiated by zinc acting as an allosteric modulator. Measurements of coronary perfusion pressure (CPP) in GPR39-null hearts using the Langendorff preparation indicate the receptor senses these eicosanoids to regulate microvascular tone. These results implicate GPR39 as an eicosanoid receptor and key regulator of myocardial tissue perfusion. Our findings will have a major impact on understanding the roles of eicosanoids in cardiovascular physiology and disease and provide an opportunity for the development of novel GPR39-targeting therapies for cardiovascular disease.

Original languageEnglish (US)
Pages (from-to)C1011-C1021
JournalAmerican Journal of Physiology - Cell Physiology
Issue number5
StatePublished - May 2022


  • EETs
  • GPCR
  • GPR39
  • HETEs
  • eicosanoids

ASJC Scopus subject areas

  • Physiology
  • Cell Biology


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