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

Abstract

G protein-coupled receptors that signal through Gα_q (G_q 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, 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 IP₃-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 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 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.

Keywords: G protein signaling; G protein-coupled receptor (GPCR); adrenergic receptor; angiotensin II; angiotensin receptor; cardiac hypertrophy; cell compartmentalization; cell signaling; intracellular compartmentalization; myocardial biology; signaling mechanism.