Gq-coupled GPCRs (Gq-receptors) produce distinct physiological responses despite common proximal signaling mechanisms, 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 inositol-1,4,5-trisphosphate-dependent intranuclear calcium required for hypertrophy. Here, we identify subcellular compartmentalization of Gq-receptor signaling as a mechanistic basis for unique Gq-receptor-induced hypertrophic phenotypes in cardiac myocytes. We show that alpha1-adrenergic receptors (a1-ARs) co-localize with phospholipase-Cbeta1 (PLCb1) and phosphatidylinositol-4,5-bisphosphate (PIP2) at the nuclear membrane. Further, nuclear a1-ARs induce intranuclear PLCb1 activity leading to the activation of perinuclear and cytosolic ERK, histone deacetylase 5 (HDAC5) export, and a robust transcriptional response. Conversely, we found that angiotensin receptors localize to the sarcolemma and induce sarcolemmal PLCb1 activity leading to the activation of cytosolic ERK, but fail to promote HDAC5 nuclear export, while producing a transcriptional response that is mostly a subset of a1-induced transcription. In summary, these results link Gq-receptor compartmentalization to unique patterns of PLCb1 activation, ERK activation, and hypertrophic transcription and significantly revise our understanding of excitation-transcription coupling.
University of Minnesota Ph.D. dissertation.March 2018. Major: Pharmacology. Advisor: Timothy O'Connell. 1 computer file (PDF); ix, 104 pages.
Compartmentalization of Proximal G alpha q-Receptor Signaling in Adult Cardiac Myocytes.
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