A aaalocked-on,aaa constitutively active mutant of the adenosine A₁ receptor

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• 作者：de Ligt ; Rianne A.F. ; Rivkees ; Scott A. ; Lorenzen ; Anna ; Leurs ; Rob ; IJzerman ; Ad P.
• 关键词：Adenosine A₁ receptor ; Inverse agonism ; Constitutive activity ; G14T mutant ; ??????Locked-on?????? phenotype
• 刊名：European Journal of Pharmacology
• 出版年：2005
• 出版时间：March 7, 2005
• 年：2005
• 卷：510
• 期：1-2
• 页码：1-8
• 全文大小：164 K

文摘

We studied the wild-type human adenosine A₁ receptor and three mutant receptors, in which the glycine at position 14 had been changed into an alanine, a leucine, or a threonine residue. All receptors were characterized in radioligand binding experiments, the wild-type and the Gly¹⁴Thr mutant receptor in greater detail. Both receptors were allosterically modulated by sodium ions and PD81,723 (2-amino-4,5-dimethyl-3-thienyl-[3(trifluoromethyl)-phenyl]methanone), although in a different way. All mutant receptors appeared to be spontaneously or “constitutively” active in a [³⁵S]GTPγS binding assay, the first demonstration of the existence of such CAM (constitutively active mutant) receptors for the adenosine A₁ receptor. The Gly¹⁴Thr mutant receptor was also constitutively active in another functional assay, i.e., the inhibition of forskolin-induced cAMP production in intact cells. Importantly, this mutant displayed a peculiar “locked-on” phenotype, i.e., neither agonist nor inverse agonist was capable of modulating the basal activity in both the GTPγS and the cAMP assay, unlike the wild-type and the two other mutant receptors.