| First Author | Dahl EF | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 23 | Pages | 8734-8749 |
| PubMed ID | 29610273 | Mgi Jnum | J:263880 |
| Mgi Id | MGI:6193478 | Doi | 10.1074/jbc.RA118.002283 |
| Citation | Dahl EF, et al. (2018) Subcellular compartmentalization of proximal Galphaq-receptor signaling produces unique hypertrophic phenotypes in adult cardiac myocytes. J Biol Chem 293(23):8734-8749 |
| abstractText | G protein-coupled receptors that signal through Galphaq (Gq receptors), such as alpha1-adrenergic receptors (alpha1-ARs) or angiotensin receptors, share a common proximal signaling pathway that activates phospholipase Cbeta1 (PLCbeta1), 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 alpha1-ARs co-localize with PLCbeta1 and PIP2 at the nuclear membrane. Further, nuclear alpha1-ARs induced intranuclear PLCbeta1 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 PLCbeta1 activity, but fail to promote HDAC5 nuclear export, while producing a transcriptional response that is mostly a subset of alpha1-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. |
