THE ALPHA(1C)-ADRENOCEPTOR IN HUMAN PROSTATE - CLONING, FUNCTIONAL EXPRESSION, AND LOCALIZATION TO SPECIFIC PROSTATIC CELL-TYPES

1 Benign prostatic hyperplasia (BPH) causes urinary obstruction in aging men that frequently requires surgery to relieve the symptoms of urinary retention, nocturia, and micturition. Smooth muscle tone which contributes to the urethral constriction in the enlarged gland appears to be mediated by the alpha(1)-adrenoceptors. In this paper, molecular and pharmacological approaches are used to establish the role played by the alpha(1C)-adrenoceptor subtype in the prostate. 2 The alpha(1)-adrenoceptor subtype(s) expressed in human prostate were investigated by use of polymerase chain reaction (PCR), Northern blot, and in situ hybridization. The alpha(1C) subtype was found in both prostate stromal and glandular cells while alpha(1B) and alpha(1D) subtypes were expressed in glandular cells. High expression levels for alpha(1C) were observed in prostate cancer tissues in both stroma and glandular cells. 3 Full length alpha(1C)-adrenoceptor cDNA was cloned from human prostate. Stable mammalian cell lines expressing human alpha(1B)-, alpha(1C)-, and alpha(1D)-adrenoceptors were made. Membranes prepared from these cell lines and human prostate were used to evaluate the pharmacological profiles of human alpha(1B)-, alpha(1C)- and alpha(1D)-adrenoceptors in comparison to human prostate. Leverage plot analysis of compound affinities determined by competition for [I-125]-I-HEAT binding demonstrated that the alpha(1C) subtype is the predominant alpha(1)-adrenoceptor in human prostate. 4 The alpha(1)-adrenoceptors cause smooth muscle constriction by coupling to IP3 turnover and intracellular Ca-2+ release. Using stable cell lines to measure IP3 production in response to noradrenaline, alpha(1C) stimulated IP3 production most efficiently, with alpha(1B) at an intermediate level, while little IP3 above background could be detected with alpha(1D). These results supported a functional role of the alpha(1C)-adrenoceptor on prostate smooth muscle constriction by noradrenaline stimulation.