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

G protein-coupled receptors that signal through Gα (G receptors), such as α-adrenergic receptors (α-ARs) or angiotensin receptors, share a common proximal signaling pathway that activates phospholipase Cβ1 (PLCβ1), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP) to produce inositol 1,4,5-trisphosphate (IP) and diacylglycerol. Despite these common proximal signaling mechanisms, G receptors produce distinct physiological responses, yet the mechanistic basis for this remains unclear. In the heart, G 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 IP-dependent intranuclear calcium required for hypertrophy. Here, we identified subcellular compartmentalization of G-receptor signaling as a mechanistic basis for unique G receptor-induced hypertrophic phenotypes in cardiac myocytes. We show that α-ARs co-localize with PLCβ1 and PIP at the nuclear membrane. Further, nuclear α-ARs induced intranuclear PLCβ1 activity, leading to histone deacetylase 5 (HDAC5) export and a robust transcriptional response ( 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-AR-induced transcription. In summary, these results link G-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-receptor localization and better explains distinct physiological functions of G receptors.