α2-Adrenoceptor Subtypes Identified by [3H]RX821002 Binding in the Human Brain: The Agonist Guanoxabenz Does Not Discriminate Different Forms of the Predominant α2A Subtype |
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Authors: | Magdalena Sastre, Jesú s A. Garcí a-Sevilla |
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Affiliation: | Laboratory of Neuropharmacology, Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, Palma de Mallorca, Spain |
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Abstract: | Abstract: Competition [3H]RX821002 ([3H]2-methoxyidazoxan) binding experiments with α2-adrenoceptor subtype-specific antagonists—BRL 44408 (α2A selective), ARC 239 (α2B selective), and others—were performed to delineate through rigorous computer modeling receptor subtypes in the postmortem human brain. In the hippocampus, hypothalamus, cerebellum, and brainstem the whole population of α2-adrenoceptors appears to belong to the α2A subtype (100%; Bmax = 34–90 fmol/mg of protein). In the frontal cortex, the predominant receptor was the α2A subtype (87%; Bmax = 53 fmol/mg of protein), although a small population of the α2B/C subtype (13%; Bmax = 8 fmol/mg of protein) was also detected. In the caudate nucleus, a mixed population of α2A (64%; Bmax = 9 fmol/mg of protein) and α2B/C (36%; Bmax = 5 fmol/mg of protein) subtypes was detected. In the cortex and caudate and in the presence of ARC 239 (to mask the α2B/C-adrenoceptors), competition experiments with the agonist guanoxabenz clearly modeled the high- and low-affinity states of the α2A subtype. In the presence of ARC 239 and the GTP analogue guanylyl-5′-imidodiphosphate together with NaCl and EDTA (to eliminate the high-affinity α2A-adrenoceptor) guanoxabenz only recognized the low-affinity α2A-adrenoceptor. The results indicate that in the human brain the predominant α2-adrenoceptor is of the α2A subtype and that this functionally relevant receptor subtype is not heterogeneous in nature. |
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Keywords: | Human brain α2-Adrenoceptor subtypes [3H]RX821002 BRL 44408 ARC 239 Guanoxabenz |
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