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Vol. 294, Issue 2, 539-547, August 2000

Agonist-Directed Trafficking of Porcine alpha 2A-Adrenergic Receptor Signaling in Chinese Hamster Ovary Cells: l-Isoproterenol Selectively Activates Gs1

Christiaan B. Brink2 , Susan M. Wade and Richard R. Neubig

Departments of Pharmacology (R.R.N., S.M.W., C.B.B.) and Internal Medicine/Hypertension (R.R.N.) and Biophysics Research Division (R.R.N.), University of Michigan, Ann Arbor, Michigan

In this study, we investigated the hypothesis of agonist-directed trafficking of receptor signaling for the alpha 2A-adrenergic receptor (alpha 2A-AR). alpha 2A-ARs couple to both Gs and Gi to stimulate or inhibit adenylyl cyclase activity. Chinese hamster ovary-K1 cell lines expressing the porcine alpha 2A-AR at high (alpha 2A-H) and low (alpha 2A-L) levels were used to estimate the relative efficacies (R.e.s) of a series of agonists for the Gs and Gi pathways. Gs-mediated responses were measured after pertussis toxin treatment to inactivate Gi in alpha 2A-H, whereas Gi responses were measured in alpha 2A-L, where Gs responses were absent. The full agonist UK-14,304 showed a large receptor reserve for Gi responses in alpha 2A-H but little receptor reserve for Gs responses in alpha 2A-H or for Gi responses in alpha 2A-L. With the exception of l-isoproterenol (ISO), all agonists showed similar R.e.s at the alpha 2A-AR for Gs and Gi responses, with rank orders of R.e.s as follows: l-epinephrine = l-norepinephrine = UK-14,304 > p-aminoclonidine >=  BHT-920 >=  BHT-933 > clonidine = p-iodoclonidine >=  xylazine >=  guanabenz. Interestingly, ISO had the highest efficacy at the alpha 2A-AR for activating Gs versus Gi (9-fold higher); however, it had low potency for both. By several criteria, the ISO response was mediated by the alpha 2A-AR, supporting the hypothesis of agonist-directed trafficking of receptor signaling or agonist-specific G protein selectivity. In contrast, the apparent Gi pathway selectivity of oxymetazoline appears to be mediated by an endogenous serotonergic receptor. It is intriguing that a classic beta -AR agonist that activates Gs through beta 2-ARs also appears to produce a Gs-selective conformation of the Gi-coupled alpha 2A-AR.

1 This work was supported by National Institutes of Health Grant HL46417 and funds from Eli Lilly (Indianapolis, IN). The development of the R3 and B2 mutants was also supported by the University of Michigan Multipurpose Arthritis Center (AR20557).

2 Present address: Division of Pharmacology, School of Pharmacy, Potchefstroom University for CHE, Potchefstroom, 2520 South Africa.

0022-3565/00/2942-0539$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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