Nuclear localization drives alpha1-adrenergic receptor oligomerization and signaling in cardiac myocytes.
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Wright CD, Wu SC, Dahl EF, Sazama AJ, O'Connell TD
Nuclear localization drives alpha1-adrenergic receptor oligomerization and signaling in cardiac myocytes.
Cell Signal. 2012 Mar;24(3):794-802. doi: 10.1016/j.cellsig.2011.11.014. Epub 2011 Nov 18.
- PubMed ID
- 22120526 [ View in PubMed]
- Abstract
Conventional models of G-protein coupled receptor (GPCR) signaling describe cell surface receptors binding to external ligands, such as hormones or circulating peptides, to induce intracellular signaling and a physiologic response. However, recent studies identify new paradigms indicating that GPCRs localize to and signal at the nucleus and that GPCR oligomers can influence receptor function. Previously, we reported that endogenous alpha1-adrenergic receptors (alpha1-ARs) localize to and signal at the nuclei in adult cardiac myocytes. In this study, we examined the mechanisms behind alpha1-AR nuclear localization and how nuclear localization impacted receptor function. We verified that endogenous alpha1-ARs localized to the nuclear membrane of intact nuclei isolated from wild-type adult cardiac myocytes. Next, we identified and disrupted putative nuclear localization sequences in both the alpha1A- and alpha1B-adrenergic receptors, which led to mis-localization of alpha1-ARs in cultured adult cardiac myocytes. Using these mutants, we demonstrated that nuclear localization was required for alpha1-signaling in adult cardiac myocytes. We also found that the nuclear export inhibitor leptomycin B inhibited alpha1-AR signaling, indicating alpha1-AR signaling must arise in the nucleus in adult cardiac myocytes. Finally, we found that co-localization of the alpha1-subtypes at the nuclei in adult cardiac myocytes facilitated the formation of receptor oligomers that could affect receptor signaling. In summary, our data indicate that alpha1-AR nuclear localization can drive the formation of receptor oligomers and regulate signaling in adult cardiac myocytes.