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CELLULAR AND MOLECULAR
1A- and 1B-Adrenoceptors Coexpressed in Human Embryonic Kidney 293 Cells
Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, Fukui, Japan
We established three human embryonic kidney (HEK) 293 cell lines stably expressing 
1-adrenoceptor (AR) subtypes, one (1A, 1B-AR) coexpressing both receptors and the other two (1A-AR and 1B-AR) expressing each receptor in isolation. In the 1A, 1B-AR cells, both receptors were clearly distinguished by the 1A-selective ligands (-)-1(3-hydroxypropyl)-5-((2R)-2-{[2-(2,2,2-trifluoroethyl]oxy]phenyl}oxy)ethyl]amino}propyl)-2,3-dihydro-1H-indole-7-carboxamide (KMD-3213) and methoxamine, but not by the subtype-nonselective ligands prazosin and phenylephrine. In all three cell lines, phenylephrine caused a concentration-dependent increase in inositol phosphates and an increase in extracellular signal-regulated kinase 1/2 (ERK1/2) activation. However, there was a 2-fold or greater maximal response to phenylephrine and a somewhat higher agonist potency in ERK1/2 activation in the 1A,1B-AR cells, compared with the responses of cells expressing either receptor individually (1A-AR or 1B-AR). Furthermore, the antagonistic affinities of prazosin (pKb of 10.1) and KMD-3213 (9.4) for inhibiting the phenylephrine response were intermediate between the values for inhibition in 1A-AR cells (prazosin, 9.3; KMD-3213, 10.5) and 1B-AR cells (prazosin, 11.0; KMD-3213, 8.1). The inhibitor pKb values in 1A, 1B-AR also differed from their ligand binding affinities measured in 1A-AR and 1B-AR cells. In contrast, the 1A-selective agonist methoxamine, which did not activate 1B-AR cells, stimulated either 1A, 1B-AR or 1A-AR cells with a comparable potency and maximum effectiveness. Our data indicate that when coexpressed in the same cell, the activation of common pathways by individual AR receptor subtypes by a nonselective agonist can exhibit enhanced responsiveness and a distinct antagonist affinity compared with the parameters for the same receptors, when expressed alone in the same cell background.
Address correspondence to: Dr. Ikunobu Muramatsu, Division of Pharmacology, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, Matsuoka, Fukui 910-1193, Japan. E-mail: muramatu{at}fmsrsa.fukui-med.ac.jp
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