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α 1a ‐Adrenoceptor polymorphism: pharmacological characterization and association with benign prostatic hypertrophy

α 1a ‐Adrenoceptor polymorphism: pharmacological characterization and association with benign... 1 Two restriction fragment length polymorphisms of the human α1a‐adrenoceptor gene digested with PstI restriction enzyme exist; the nucleotide change causes the substitution of C residue for T at nucleotide 1441, thereby Arg492 to Cys492 transition, which might confer an additional putative palmitoylation site in the carboxy‐terminal segment of the α1a‐adrenoceptor. In the present study, we compared their pharmacological properties and examined whether this α1a‐adrenoceptor polymorphism is associated with benign prostatic hypertrophy (BPH). 2 The frequency of α1a‐adrenoceptor polymorphism was not differently distributed between patients with benign prostatic hypertrophy (BPH) and normal subjects in Japan; thus, the relative frequencies of the C and T alleles were 0.90: 0.10 in normal male subjects (n = 45) and 0.87: 0.13 in BPH patients (n = 222), respectively. However, the frequency distribution of this polymorphism was significantly different between the Japanese and U.S. populations; thus, C and T alleles were 0.34 and 0.66 in U.S. populations. 3 Utilizing Chinese hamster ovary (CHO) cells stably expressing the two polymorphic α1a‐adrenoceptors (Arg492 and Cys492), we compared their binding affinity and signal transduction. Radioligand binding studies with 2‐(β‐(4‐hydroxy‐3(125I)‐iodophenyl) ethylamino‐methyl)tetralone ((125I)‐HEAT) showed no marked difference in the antagonist or agonist binding affinities between the two receptors. Also, both receptors were found to be coupled to the calcium signaling, and the concentration‐cytosolic Ca2+ concentrations ((Ca2+)i response relationships for noradrenaline were similar for the two polymorphic receptors. Furthermore, the receptor‐mediated (Ca2+)i response was markedly desensitized after a 2 h exposure of phenylephrine (10 μm), and the extent of the desensitization was not significantly different between the two receptors. 4 In summary, the results showed that the two α1a‐adrenoceptors generated by genetic polymorphism have similar pharmacological characteristics, and the receptor‐mediated (Ca2+)i response can be desensitized in a similar manner. The study did not provide any evidence to support the hypothesis that α1a‐adrenoceptor gene polymorphism is associated with BPH. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

α 1a ‐Adrenoceptor polymorphism: pharmacological characterization and association with benign prostatic hypertrophy

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References (29)

Publisher
Wiley
Copyright
1996 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1111/j.1476-5381.1996.tb15552.x
Publisher site
See Article on Publisher Site

Abstract

1 Two restriction fragment length polymorphisms of the human α1a‐adrenoceptor gene digested with PstI restriction enzyme exist; the nucleotide change causes the substitution of C residue for T at nucleotide 1441, thereby Arg492 to Cys492 transition, which might confer an additional putative palmitoylation site in the carboxy‐terminal segment of the α1a‐adrenoceptor. In the present study, we compared their pharmacological properties and examined whether this α1a‐adrenoceptor polymorphism is associated with benign prostatic hypertrophy (BPH). 2 The frequency of α1a‐adrenoceptor polymorphism was not differently distributed between patients with benign prostatic hypertrophy (BPH) and normal subjects in Japan; thus, the relative frequencies of the C and T alleles were 0.90: 0.10 in normal male subjects (n = 45) and 0.87: 0.13 in BPH patients (n = 222), respectively. However, the frequency distribution of this polymorphism was significantly different between the Japanese and U.S. populations; thus, C and T alleles were 0.34 and 0.66 in U.S. populations. 3 Utilizing Chinese hamster ovary (CHO) cells stably expressing the two polymorphic α1a‐adrenoceptors (Arg492 and Cys492), we compared their binding affinity and signal transduction. Radioligand binding studies with 2‐(β‐(4‐hydroxy‐3(125I)‐iodophenyl) ethylamino‐methyl)tetralone ((125I)‐HEAT) showed no marked difference in the antagonist or agonist binding affinities between the two receptors. Also, both receptors were found to be coupled to the calcium signaling, and the concentration‐cytosolic Ca2+ concentrations ((Ca2+)i response relationships for noradrenaline were similar for the two polymorphic receptors. Furthermore, the receptor‐mediated (Ca2+)i response was markedly desensitized after a 2 h exposure of phenylephrine (10 μm), and the extent of the desensitization was not significantly different between the two receptors. 4 In summary, the results showed that the two α1a‐adrenoceptors generated by genetic polymorphism have similar pharmacological characteristics, and the receptor‐mediated (Ca2+)i response can be desensitized in a similar manner. The study did not provide any evidence to support the hypothesis that α1a‐adrenoceptor gene polymorphism is associated with BPH.

Journal

British Journal of PharmacologyWiley

Published: Jul 1, 1996

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