Nuclear α1-adrenergic receptors signal activated ERK localization to caveolae in adult cardiac myocytes

Casey D. Wright, Quanhai Chen, Nichole L. Baye, Yuan Huang, Chastity L. Healy, Sivakanthan Kasinathan, Timothy D. O'Connell

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

We previously identified an α1-AR-ERK (α1A-adrenergic receptor-extracellular signal-regulated kinase) survival signaling pathway in adult cardiac myocytes. Here, we investigated localization of α1-AR subtypes (α1A and α1B) and how their localization influences α1-AR signaling in cardiac myocytes. Using binding assays on myocyte subcellular fractions or a fluorescent α1-AR antagonist, we localized endogenous α1-ARs to the nucleus in wild-type adult cardiac myocytes. To clarify α1 subtype localization, we reconstituted α1 signaling in cultured α1A- and α1B-AR double knockout cardiac myocytes using α1-AR-green fluorescent protein (GFP) fusion proteins. Similar to endogenous α1-ARs and α1A- and α1B-GFP colocalized with LAP2 at the nuclear membrane. α1-AR nuclear localization was confirmed in vivo using α1-AR-GFP transgenic mice. The α1-signaling partners Gαq and phospholipase Cβ1 also colocalized with α1-ARs only at the nuclear membrane. Furthermore, we observed rapid catecholamine uptake mediated by norepinephrine-uptake-2 and found that α1-mediated activation of ERK was not inhibited by a membrane impermeant α1-blocker, suggesting α1 signaling is initiated at the nucleus. Contrary to prior studies, we did not observe α1-AR localization to caveolae, but we found that α1-AR signaling initiated at the nucleus led to activated ERK localized to caveolae. In summary, our results show that nuclear α1-ARs transduce signals to caveolae at the plasma membrane in cardiac myocytes.

Original languageEnglish (US)
Pages (from-to)992-1000
Number of pages9
JournalCirculation research
Volume103
Issue number9
DOIs
StatePublished - Oct 24 2008

Keywords

  • Cardiac myocytes
  • ERK
  • α1-adrenergic receptors

Fingerprint Dive into the research topics of 'Nuclear α1-adrenergic receptors signal activated ERK localization to caveolae in adult cardiac myocytes'. Together they form a unique fingerprint.

  • Cite this