Regulated expression of pH sensing G protein-coupled receptor-68 identified through chemical biology defines a new drug target for ischemic heart disease

Jamie L. Russell, Sean C. Goetsch, Hector R. Aguilar, Helen Coe, Xiang Luo, Ning Liu, Eva Van Rooij, Doug E. Frantz, Jay W. Schneider

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Chemical biology promises discovery of new and unexpected mechanistic pathways, protein functions and disease targets. Here, we probed the mechanism-of-action and protein targets of 3,5-disubstituted isoxazoles (Isx), cardiomyogenic small molecules that target Notch-activated epicardium-derived cells (NECs) in vivo and promote functional recovery after myocardial infarction (MI). Mechanistic studies in NECs led to an Isx-activated G q protein-coupled receptor (G qPCR) hypothesis tested in a cell-based functional target screen for GPCRs regulated by Isx. This screen identified one agonist hit, the extracellular proton/pH-sensing GPCR GPR68, confirmed through genetic gain- and loss-of-function. Overlooked until now, GPR68 expression and localization were highly regulated in early post-natal and adult post-infarct mouse heart, where GPR68-expressing cells accumulated subepicardially. Remarkably, GPR68-expressing cardiomyocytes established a proton-sensing cellular "buffer zone" surrounding the MI. Isx pharmacologically regulated gene expression (mRNAs and miRs) in this GPR68-enriched border zone, driving cardiomyogenic and pro-survival transcriptional programs in vivo. In conclusion, we tracked a (micromolar) bioactive small molecules mechanism-of-action to a candidate target protein, GPR68, and validated this target as a previously unrecognized regulator of myocardial cellular responses to tissue acidosis, setting the stage for future (nanomolar) target-based drug lead discovery.

Original languageEnglish (US)
Pages (from-to)1077-1083
Number of pages7
JournalACS chemical biology
Volume7
Issue number6
DOIs
StatePublished - Jun 15 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

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