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 agi ng men that frequently requires surgery to relieve the symptoms of uri nary retention, nocturia, and micturition. Smooth muscle tone which co ntributes to the urethral constriction in the enlarged gland appears t o be mediated by the alpha(1)-adrenoceptors. In this paper, molecular and pharmacological approaches are used to establish the role played b y the alpha(1C)-adrenoceptor subtype in the prostate. 2 The alpha(1)-a drenoceptor subtype(s) expressed in human prostate were investigated b y use of polymerase chain reaction (PCR), Northern blot, and in situ h ybridization. The alpha(1C) subtype was found in both prostate stromal and glandular cells while alpha(1B) and alpha(1D) subtypes were expre ssed in glandular cells. High expression levels for alpha(1C) were obs erved in prostate cancer tissues in both stroma and glandular cells. 3 Full length alpha(1C)-adrenoceptor cDNA was cloned from human prostat e. 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 pharmacologic al profiles of human alpha(1B)-, alpha(1C)- and alpha(1D)-adrenoceptor s in comparison to human prostate. Leverage plot analysis of compound affinities determined by competition for [I-125]-I-HEAT binding demons trated that the alpha(1C) subtype is the predominant alpha(1)-adrenoce ptor in human prostate. 4 The alpha(1)-adrenoceptors cause smooth musc le constriction by coupling to IP3 turnover and intracellular Ca-2+ re lease. Using stable cell lines to measure IP3 production in response t o noradrenaline, alpha(1C) stimulated IP3 production most efficiently, with alpha(1B) at an intermediate level, while little IP3 above backg round could be detected with alpha(1D). These results supported a func tional role of the alpha(1C)-adrenoceptor on prostate smooth muscle co nstriction by noradrenaline stimulation.