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

• Published in: The Journal of biological chemistry Vol. 293; no. 23; pp. 8734 - 8749
• Main Authors: Dahl, Erika F., Wu, Steven C., Healy, Chastity L., Harsch, Brian A., Shearer, Gregory C., O’Connell, Timothy D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.06.2018; American Society for Biochemistry and Molecular Biology
• Subjects: Active Transport, Cell Nucleus; adrenergic receptor; angiotensin II; angiotensin receptor; Animals; cardiac hypertrophy; Cardiomegaly - genetics; Cardiomegaly - metabolism; Cardiomegaly - pathology; cell compartmentalization; Cell Nucleus - metabolism; Cell Nucleus - pathology; cell signaling; Female; G protein signaling; G protein-coupled receptor (GPCR); GTP-Binding Protein alpha Subunits, Gq-G11 - analysis; GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism; Histone Deacetylases - analysis; Histone Deacetylases - metabolism; intracellular compartmentalization; Male; Mice, Inbred C57BL; myocardial biology; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Nuclear Envelope - metabolism; Nuclear Envelope - pathology; Phenotype; Phosphatidylinositol 4,5-Diphosphate - analysis; Phosphatidylinositol 4,5-Diphosphate - metabolism; Phospholipase C beta - analysis; Phospholipase C beta - metabolism; Receptors, Adrenergic, alpha-1 - analysis; Receptors, Adrenergic, alpha-1 - metabolism; Sarcolemma - metabolism; Sarcolemma - pathology; Signal Transduction; signaling mechanism; Transcriptional Activation; signaling mechanism; G protein signaling; angiotensin receptor; myocardial biology; cell compartmentalization; angiotensin II; cell signaling; G protein-coupled receptor (GPCR); adrenergic receptor; cardiac hypertrophy; intracellular compartmentalization
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA118.002283

G protein–coupled receptors that signal through Gαq (Gq receptors), such as α1-adrenergic receptors (α1-ARs) or angiotensin receptors, share a common proximal signaling pathway that activates phospholipase Cβ1 (PLCβ1), 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 that α1-ARs co-localize with PLCβ1 and PIP2 at the nuclear membrane. Further, nuclear α1-ARs induced intranuclear PLCβ1 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 PLCβ1 activity, but fail to promote HDAC5 nuclear export, while producing a transcriptional response that is mostly a subset of α1-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.