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 affinity and signal transduction. Radioligand binding studies with 2-[beta-(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 microM), 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.
Shibata
K
K
Department of Molecular, Cell Pharmacology, National Children's Medical Research Center, Tokyo, Japan.
Hirasawa
A
A
Moriyama
N
N
Kawabe
K
K
Ogawa
S
S
Tsujimoto
G
G
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D003001:Cloning, Molecular; D006224:Cricetinae; D005838:Genotype; D006358:Hot Temperature; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011470:Prostatic Hyperplasia / Q000235:genetics* / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
D018340:Receptors, Adrenergic, alpha-1; D002118:Calcium