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J. Biol. Chem., Vol. 278, Issue 41, 39773-39781, October 10, 2003

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Resistance of the Human ₁-Adrenergic Receptor to Agonist-mediated Down-regulation

ROLE OF THE C TERMINUS IN DETERMINING -SUBTYPE DEGRADATION^*

Wei Liang, Steven Austin , Quang Hoang and Peter H. Fishman 

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

Prolonged agonist stimulation results in down-regulation of most G protein-coupled receptors. When we exposed baby hamster kidney cells stably expressing the human ₁-adrenergic receptor (₁AR) to agonist over a 24-h period, we instead observed an increase of 30% in both ₁AR binding activity and immune-detected receptors. In contrast, ₂AR expressed in these cells exhibited a decrease of 50%. We determined that the basal turnover rates of the two subtypes were similar (t 7 h) and that agonist stimulation increased ₂AR but not ₁AR turnover. Blocking receptor trafficking to lysosomes with bafilomycin A₁ had no effect on basal turnover of either subtype but blocked agonist-stimulated ₂AR turnover. As ₁AR mRNA levels increased in agonist-stimulated cells, ₁AR up-regulation appeared to result from increased synthesis with no change in degradation. To explore the basis for the subtype differences, we expressed chimeras in which the C termini had been exchanged. Each chimera responded to persistent agonist stimulation based on the source of its C-tail; ₁AR with a ₂AR C-tail underwent down-regulation, and ₂AR with a ₁AR C-tail underwent up-regulation. The C-tails had a corresponding effect on agonist-stimulated receptor phosphorylation and internalization with the order being ₂AR > ₁AR with ₂AR C-tail > ₂AR with a ₁AR C-tail > ₁AR. As internalization may be a prerequisite for down-regulation, we addressed this possibility by co-expressing each subtype with arrestin-2. Although ₁AR internalization was increased to that of ₂AR, down-regulation still did not occur. Instead, ₁AR accumulated inside the cells. We conclude that in unstimulated cells, both subtypes appear to be turned over by the same mechanism. Upon agonist stimulation, both subtypes are internalized, and ₂AR but not ₁AR undergoes lysosomal degradation, the fate of each subtype being regulated by determinants in its C-tail.

Received for publication, April 29, 2003 , and in revised form, July 21, 2003.

^* 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.

Present address: Dept. of Psychology, State University of Arizona, Tempe, AZ 85287.

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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