Nuclear localization drives α1-adrenergic receptor oligomerization and signaling in cardiac myocytes

Casey D. Wright, Steven C. Wu, Erika F. Dahl, Alan J. Sazama, Timothy D. O'Connell

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


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 α1-adrenergic receptors (α1-ARs) localize to and signal at the nuclei in adult cardiac myocytes. In this study, we examined the mechanisms behind α1-AR nuclear localization and how nuclear localization impacted receptor function. We verified that endogenous α1-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 α1A- and α1B-adrenergic receptors, which led to mis-localization of α1-ARs in cultured adult cardiac myocytes. Using these mutants, we demonstrated that nuclear localization was required for α1-signaling in adult cardiac myocytes. We also found that the nuclear export inhibitor leptomycin B inhibited α1-AR signaling, indicating α1-AR signaling must arise in the nucleus in adult cardiac myocytes. Finally, we found that co-localization of the α1-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 α1-AR nuclear localization can drive the formation of receptor oligomers and regulate signaling in adult cardiac myocytes.

Original languageEnglish (US)
Pages (from-to)794-802
Number of pages9
JournalCellular Signalling
Issue number3
StatePublished - Mar 2012

Bibliographical note

Funding Information:
This work was supported by grants from the National Institute of Health ( P20 RR-017662 , TDO; F32 HL085980-02 , CDW). The authors would also like to thank Chastity L. Healy, Kelly Graber of the Sanford Research Imaging Core, Andy Cypher of the Sanford Research Cell Culture Core, and Yuan Huang, MD of the Sanford Research Molecular Biology Core for their excellent technical assistance. The Sanford Research Cores listed here were supported by a grant from the National Institutes of Health (P20 RR-017662).


  • Cardiac myocyte
  • ERK
  • G protein-coupled receptor
  • Oligomer
  • α1-adrenergic receptor


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