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Alpha 1a-adrenoceptor polymorphism: pharmacological characterization and association with benign prostatic
K Shibata1, A Hirasawa, N Moriyama
1Department of Molecular, Cell Pharmacology, National Children's Medical Research Center, Tokyo, Japan.
British Journal of Pharmacology
|July 1, 1996
Summary
Genetic variations in the alpha 1a-adrenoceptor gene do not appear to be linked to benign prostatic hypertrophy (BPH). These alpha 1a-adrenoceptor polymorphisms exhibit similar pharmacological properties and signaling responses.
Area of Science:
- Pharmacology
- Genetics
- Urology
Background:
- Two common polymorphisms in the human alpha 1a-adrenoceptor gene result from a C to T nucleotide change at position 1441, leading to an Arg492 to Cys492 amino acid substitution.
- This substitution may create an additional palmitoylation site in the alpha 1a-adrenoceptor's carboxy-terminal segment.
- The association between this alpha 1a-adrenoceptor gene polymorphism and benign prostatic hypertrophy (BPH) requires investigation.
Purpose of the Study:
- To compare the pharmacological properties of the two alpha 1a-adrenoceptor variants (Arg492 and Cys492).
- To determine if the alpha 1a-adrenoceptor gene polymorphism is associated with benign prostatic hypertrophy (BPH).
Main Methods:
- Genotyping of alpha 1a-adrenoceptor polymorphisms in Japanese BPH patients and normal subjects, and comparison with U.S. population data.
- Stable expression of Arg492 and Cys492 alpha 1a-adrenoceptors in Chinese hamster ovary (CHO) cells.
- Radioligand binding assays using [125I]-HEAT to assess antagonist and agonist binding affinities.
- Measurement of intracellular calcium ([Ca2+]i) responses to noradrenaline and phenylephrine to evaluate signal transduction and desensitization.
Main Results:
- The frequency of the alpha 1a-adrenoceptor polymorphism did not differ significantly between Japanese BPH patients and normal individuals (allele frequencies C:T were 0.87:0.13 in BPH patients and 0.90:0.10 in controls).
- Significant differences in allele frequencies were observed between Japanese (C:T = 0.87:0.13) and U.S. populations (C:T = 0.34:0.66).
- Pharmacological studies in CHO cells revealed no significant differences in binding affinities or noradrenaline-induced calcium signaling between the Arg492 and Cys492 receptors. Receptor-mediated calcium responses showed similar desensitization patterns for both variants.
Conclusions:
- The two alpha 1a-adrenoceptor variants resulting from the studied genetic polymorphism exhibit comparable pharmacological characteristics and signal transduction pathways.
- The alpha 1a-adrenoceptor gene polymorphism investigated is not associated with benign prostatic hypertrophy (BPH) in the Japanese population studied.
- The findings do not support a link between this specific alpha 1a-adrenoceptor polymorphism and the development of BPH.