In clinical Urology, muscarinic drug therapy with both agonists (bethanechol) and antagonists (oxybutynin) is used to a considerable extent. However, the function of the muscarinic receptors in the bladder have not been unequivocally determined at the subtype level. This is an important distinction since it appears that the cellular response to neuronally released acetylcholine can be either excitatory or inhibitory, perhaps depending on the muscarinic receptor subtype stimulated. On the basis of the action of antagonists 3 muscarinic receptor subtypes (designated by upper case """"""""M"""""""", M1 - M3) can be defined although none of the antagonists yet studied is highly selective for one receptor subtype over all of the others. Therefore previous pharmacological characterization of muscarinic receptor subtypes represents the composite properties of a heterogenous mixture of receptor subtypes. Two recent, interrelated advances have made it possible to determine the density, cellular location and physiological regulation of muscarinic receptor subtypes: the cloning of genes for muscarinic receptor subtypes and development of subtype specific antibodies. The molecular biology approach has resulted in the cloning of a family of muscarinic genes which share the same proposed overall structure and a large degree of protein sequence homology. Five muscarinic receptors (designated by lower case """"""""m"""""""", m1-m5) are known and there are indications that more may exist. Our previous studies have determined that two subtypes of muscarinic receptor (m2 and m3) are present in bladder tissue from rat, rabbit, guinea pig, and human, suggesting that one or both may be involved in bladder contractility. These receptors mediate their effects through different biochemical mechanisms, and presumably the regulation of receptor levels and activity are independent since our previous studies have shown differential regulation of the two subtypes under various experimental conditions. We will attempt to identify which subtype of receptor regulates bladder contractility, and more closely examine the biochemical events associated with receptor activation. These studies should elucidate potential mechanisms by which bladder muscarinic receptor levels and activity are regulated, and determine which mechanisms allow selective regulation of individual receptor subtypes. The long range goal of this project is to define the role of the different muscarinic receptor subtypes in bladder function.
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