Urinary Incontinence and Mutation of β_3 Adrenoceptor Gene

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A miss-sense mutation in codon 64 of the β_3-adrenoceptor(AR) occurs with some frequency. Because activation of the β_3-AR causes a relaxation of detrusor muscle, we hypothesized that this mutation may be involved in idiopathic overactive bladder(OAB), leading to urge incontinence. The present study was therefore undertaken to investigate the above possibility.We showed that the mRNA of α_<1a>,α_<1b>,α_<1d>, β_1 and β_2-AR was expressed at low levels, while β_3-AR was the most highly expressed subtype(approximately 94% of the overall messages) in human bladder. This predominant β_3-AR plays an essential role in relaxation of the bladder during urine storage.We also investigated the mechanisms of relaxation via β_3-AR in detrusor muscle. Our results suggest that in addition to cAMP-dependent pathway, BKca channels are involved in the β_3-AR agonists-induced relaxation in pre-contracted detrusor muscle.The studies, using CHO-K1 cells that express human β_3-AR and its mutant β_3AR, showed that there was no significant difference between wild type and mutation in terms of binding characteristics and cAMP production.However, these findings can not be directly transferred to the in vivo situation.Frinally, in large scale clinical study, we obtained hair root samples from 100 patients with idiopathic OAB and 101 non-OAB control volumteers. We found that the overall frequency of the β_3-AR gene mutation was 47% in the OAB patients, which was much higher than the mutation frequency of 22.8% in non-OAB control. These results provide support for our hypothesis that dysfunction of β_3-AR resulting from its gene mutation may be responsible for developing OAB symptoms. Thus, the β_3-AR polymorphism may be used as a genetic marker for OAB.