Nuclear Localization of α1A-Adrenergic Receptors Is Required for Signaling in Cardiac Myocytes: An "Inside-Out" α1-AR Signaling Pathway. an " inside-out" a1-AR signaling pathway.

Steven C. Wu, Erika F. Dahl, Casey D. Wright, Andrew L. Cypher, Chastity L. Healy, Timothy D. O'Connell

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Recent studies indicate that a1-adrenergic receptors (a1-ARs) are cardioprotective by preventing cardiac myocyte death and augmenting contractility in heart failure. Although G-protein-coupled receptors are assumed to localize to and signal at the plasma membrane, we previously demonstrated that endogenous a1-ARs localize to the nuclei in adult cardiac myocytes. However, the functional consequence of this nuclear localization remains unclear. Here, we attempted to reconcile nuclear localization of a1-ARs with their physiologic function by examining a1-AR-induced contractility in adult cardiac myocytes. By measuring shortening in unloaded, cultured adult cardiac myocytes, we found that the a1A-subtype regulated contractility through phosphorylation of cardiac troponin I (cTnI) at the protein kinase C (PKC) site, threonine 144. Reconstitution of an a1A-subtype nuclear localization mutant in cardiac myocytes lacking a1-ARs failed to rescue nuclear a1A-mediated phosphorylation of cTnI and myocyte contractility. Leptomycin B, the nuclear export inhibitor, also blocked a1A-mediated phosphorylation of cTnI. These data indicate that a1-AR signaling originates in the nucleus. Consistent with these observations, we localized the a1A-subtype to the inner nuclear membrane, identified PKCa, d, and e in the nucleus, and found that a1-ARs activate PKCd in nuclei isolated from adult cardiac myocytes. Finally, we found that a PKCd nuclear localization mutant blunted a1-induced phosphorylation of cTnI. Together, our data identify a novel, " inside-out" nuclear a1A-subtype/PKCd/cTnI-signaling pathway that regulates contractile function in adult cardiac myocytes. Importantly, these data help resolve the discrepancy between nuclear localization of a1-ARs and a1-AR-mediated physiologic function.

Original languageEnglish (US)
Pages (from-to)000145
JournalJournal of the American Heart Association
Volume3
Issue number2
DOIs
StatePublished - 2014

Fingerprint Dive into the research topics of 'Nuclear Localization of α1A-Adrenergic Receptors Is Required for Signaling in Cardiac Myocytes: An "Inside-Out" α1-AR Signaling Pathway. an " inside-out" a1-AR signaling pathway.'. Together they form a unique fingerprint.

  • Cite this