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(Circulation Research. 2008;103:992.)
© 2008 American Heart Association, Inc.

Cellular Biology

Nuclear 1-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

From the Cardiovascular Research Center, Sanford Research/University of South Dakota, Sioux Falls.

Correspondence to Timothy D. O'Connell, Cardiovascular Research Center, Sanford Research/USD, 1100 E 21st St, Suite 700, Sioux Falls, SD 57105. E-mail oconnelt{at}sanfordhealth.org

We previously identified an 1-AR-ERK (1A-adrenergic receptor–extracellular signal-regulated kinase) survival signaling pathway in adult cardiac myocytes. Here, we investigated localization of 1-AR subtypes (1A and 1B) and how their localization influences 1-AR signaling in cardiac myocytes. Using binding assays on myocyte subcellular fractions or a fluorescent 1-AR antagonist, we localized endogenous 1-ARs to the nucleus in wild-type adult cardiac myocytes. To clarify 1 subtype localization, we reconstituted 1 signaling in cultured 1A- and 1B-AR double knockout cardiac myocytes using 1-AR–green fluorescent protein (GFP) fusion proteins. Similar to endogenous 1-ARs and 1A- and 1B-GFP colocalized with LAP2 at the nuclear membrane. 1-AR nuclear localization was confirmed in vivo using 1-AR-GFP transgenic mice. The 1-signaling partners Gq and phospholipase Cβ1 also colocalized with 1-ARs only at the nuclear membrane. Furthermore, we observed rapid catecholamine uptake mediated by norepinephrine-uptake-2 and found that 1-mediated activation of ERK was not inhibited by a membrane impermeant 1-blocker, suggesting 1 signaling is initiated at the nucleus. Contrary to prior studies, we did not observe 1-AR localization to caveolae, but we found that 1-AR signaling initiated at the nucleus led to activated ERK localized to caveolae. In summary, our results show that nuclear 1-ARs transduce signals to caveolae at the plasma membrane in cardiac myocytes.

Key Words: 1-adrenergic receptors • cardiac myocytes • ERK