Subcellular compartmentalization of proximal Gα(q)-receptor signaling produces unique hypertrophic phenotypes in adult cardiac myocytes

G protein–coupled receptors that signal through Gα(q) (G(q) receptors), such as α(1)-adrenergic receptors (α(1)-ARs) or angiotensin receptors, share a common proximal signaling pathway that activates phospholipase Cβ1 (PLCβ1), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP(2)) to produce inositol 1,4,5-trisphosphate (IP(3)) and diacylglycerol. Despite these common proximal signaling mechanisms, G(q) receptors produce distinct physiological responses, yet the mechanistic basis for this remains unclear. In the heart, G(q) 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 IP(3)-dependent intranuclear calcium required for hypertrophy. Here, we identified subcellular compartmentalization of G(q)-receptor signaling as a mechanistic basis for unique G(q) receptor–induced hypertrophic phenotypes in cardiac myocytes. We show that α(1)-ARs co-localize with PLCβ1 and PIP(2) at the nuclear membrane. Further, nuclear α(1)-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 α(1)-AR–induced transcription. In summary, these results link G(q)-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 G(q)-receptor localization and better explains distinct physiological functions of G(q) receptors.