alpha(1a)-adrenoceptor polymorphism: Pharmacological characterization and association with benign prostatic hypertrophy

1 Two restriction fragment length polymorphisms of the human alpha(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 alpha(1a),-adrenoceptor. In the present study, we compared their pharmacological properties and examined whether this alpha(1a),-adrenoceptor polymorphism is associated with benign prostatic hypertrophy (BPH). 2 The frequency of alpha(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 alpha(1a)-adrenoceptors (Arg492 and Cys492), we compared their binding affiinity and signal transduction. Radioligand binding studies with 2-[beta-(4-hydroxy-3[I-125]-iodophenyl) ethylamino-methyl]tetralone ([I-125]- 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 mu M), and the extent of the desensitization was not significantly different between the two receptors. 4 In summary, the results showed that the two alpha(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 alpha(1a)-adrenoceptor gene polymorphism is associated with BPH.