Subcellular compartmentalization of proximal Gq-receptor signaling produces unique hypertrophic phenotypes in adult cardiac myocytes

Erika F. Dahl, Steven C. Wu, Chastity L. Healy, Brian A. Harsch, Gregory C. Shearer, Timothy D. O’Connell

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

G protein– coupled receptors that signal through Gq (Gq receptors), such as1-adrenergic receptors (1-ARs) or angiotensin receptors, share a common proximal signaling pathway that activates phospholipase C1 (PLC1), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) to produce inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. Despite these common proximal signaling mechanisms, Gq receptors produce distinct physiological responses, yet the mechanistic basis for this remains unclear. In the heart, Gq receptors are thought to induce myocyte hypertrophy through a mechanism termed excitation–transcription coupling, which provides a mechanistic basis for compartmentalization of calcium required for contraction versus IP3-dependent intranuclear calcium required for hypertrophy. Here, we identified subcellular compartmentalization of Gq-receptor signaling as a mechanistic basis for unique Gq receptor–induced hypertrophic phenotypes in cardiac myocytes. We show that1-ARs co-localize with PLC1 and PIP2 at the nuclear membrane. Further, nuclear1-ARs induced intranuclear PLC1 activity, leading to histone deacetylase 5 (HDAC5) export and a robust transcriptional response (i.e. significant up- or down-regulation of 806 genes). Conversely, we found that angiotensin receptors localize to the sarcolemma and induce sarcolemmal PLC1 activity, but fail to promote HDAC5 nuclear export, while producing a transcriptional response that is mostly a subset of1-AR–induced transcription. In summary, these results link Gq-receptor compartmentalization in cardiac myocytes to unique hypertrophic transcription. They suggest a new model of excitation–transcription coupling in adult cardiac myocytes that accounts for differential Gq-receptor localization and better explains distinct physiological functions of Gq receptors.

Original languageEnglish (US)
Pages (from-to)8734-8749
Number of pages16
JournalJournal of Biological Chemistry
Volume293
Issue number23
DOIs
StatePublished - Jun 8 2018

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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