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

5 Citations (Scopus)

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 - Jan 1 2018

Fingerprint

Cardiac Myocytes
Phenotype
Angiotensin Receptors
Histone Deacetylases
Transcription
Hypertrophy
Calcium
Sarcolemma
Inositol 1,4,5-Trisphosphate
Cell Nucleus Active Transport
Diglycerides
Nuclear Envelope
G-Protein-Coupled Receptors
Phosphatidylinositols
Adrenergic Receptors
Muscle Cells
Up-Regulation
Down-Regulation
Genes
Membranes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Dahl, Erika F. ; Wu, Steven C. ; Healy, Chastity L. ; Harsch, Brian A. ; Shearer, Gregory C. ; O’Connell, Timothy D. / Subcellular compartmentalization of proximal Gq-receptor signaling produces unique hypertrophic phenotypes in adult cardiac myocytes. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 23. pp. 8734-8749.
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Subcellular compartmentalization of proximal Gq-receptor signaling produces unique hypertrophic phenotypes in adult cardiac myocytes. / Dahl, Erika F.; Wu, Steven C.; Healy, Chastity L.; Harsch, Brian A.; Shearer, Gregory C.; O’Connell, Timothy D.

In: Journal of Biological Chemistry, Vol. 293, No. 23, 01.01.2018, p. 8734-8749.

Research output: Contribution to journalArticle

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T1 - Subcellular compartmentalization of proximal Gq-receptor signaling produces unique hypertrophic phenotypes in adult cardiac myocytes

AU - Dahl, Erika F.

AU - Wu, Steven C.

AU - Healy, Chastity L.

AU - Harsch, Brian A.

AU - Shearer, Gregory C.

AU - O’Connell, Timothy D.

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AB - 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.

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