α1a‐Adrenoceptor polymorphism: pharmacological characterization and association with benign prostatic hypertrophy

Abstract

1 Two restriction fragment length polymorphisms of the human α_1a-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 α_1a-adrenoceptor. In the present study, we compared their pharmacological properties and examined whether this α_1a-adrenoceptor polymorphism is associated with benign prostatic hypertrophy (BPH). 2 The frequency of α_1a-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 α_1a-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 α_1a-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 α_1a-adrenoceptor gene polymorphism is associated with BPH.