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J. Biol. Chem., Vol. 279, Issue 45, 46882-46889, November 5, 2004

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Resistance of the Human ₁-Adrenergic Receptor to Agonist-induced Ubiquitination

A MECHANISM FOR IMPAIRED RECEPTOR DEGRADATION^*

Wei Liang and Peter H. Fishman

From the Membrane Biochemistry Section, Laboratory of Molecular and Cellular Neurobiology, NINDS, National Institutes of Health, Bethesda, Maryland 20892

Down-regulation is a classic response of most G protein-coupled receptors to prolonged agonist stimulation. We recently showed that when expressed in baby hamster kidney cells, the human ₁-but not the ₂-adrenergic receptor (AR) is totally resistant to agonist-mediated down-regulation, whereas both have similar rates of basal degradation (Liang, W., Austin, S., Hoang, Q., and Fishman, P. H. (2003) J. Biol. Chem. 278, 39773–39781). To identify the underlying mechanism(s) for this resistance, we investigated the role of proteasomes, lysosomes, and ubiquitination in the degradation of ₁AR expressed in baby hamster kidney and human embryonic kidney 293 cells. Both lysosomal and proteasomal inhibitors reduced ₁AR degradation in agonist-stimulated cells but were less effective on basal degradation. To determine whether ₁AR trafficked to lysosomes we used confocal fluorescence microscopy. We observed some colocalization of ₁AR and lysosomal markers in agonist-treated cells but much less than that of ₂AR even in cells co-transfected with arrestin-2, which increases ₁AR internalization. Ubiquitination of ₂AR readily occurred in agonist-stimulated cells, whereas ubiquitination of ₁AR was not detectable even under conditions optimal for that of ₂AR. Moreover, in cells expressing AR chimeras in which the C termini have been switched, the chimeric ₁AR with ₂AR C-tail underwent ubiquitination and down-regulation, but the chimeric ₂AR with ₁AR C-tail did not. Our results demonstrate for the first time that ₁AR and ₂AR differ in the ability to be ubiquitinated. Because ubiquitin serves as a signal for sorting membrane receptors to lysosomes, the lack of agonist-mediated ubiquitination of ₁AR may prevent its extensive trafficking to lysosomes and, thus, account for its resistance to down-regulation.

Received for publication, June 11, 2004 , and in revised form, July 28, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Bldg. 49, Rm. 2A28, 49 Convent Dr., MSC4440, NIH, Bethesda, MD 20892-4440. Tel.: 301-496-1325; Fax: 301-496-8244; E-mail: fishmanp{at}ninds.nih.gov.

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