Abstract
An understanding of muscarinic receptors is tantamount to an understanding of overactive bladder. The M3 muscarinic receptor subtype is responsible for detrusor smooth muscle contraction and it exerts an exocrine function in the salivary glands. Alterations in the receptor’s response to acetylcholine as a result of injury may lead to hypersensitivity and overactivity. The M2 receptor subtype, which is mainly responsible for cardiac function, is the muscarinic receptor of highest proportion in the detrusor. M2 also may play a role in detrusor contraction in injury and pathologic states. Muscarinic antagonists are the mainstay of pharmacotherapy for overactive bladder, but those that are available are not tissue specific. Growing knowledge of the nuances of receptor-ligand behavior and interaction between muscarinic receptors subtypes may provide novel targets for future drug development, improve efficacy, and reduce bothersome side effects.
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References and Recommended Reading
Caulfield MP, Birdsall NJ: International union of pharmacology. XVII: classification of muscarinic acetylcholine receptors. Pharmacol Rev 1998, 50:279–290.
Eglen RM, Nahorski SR: The muscarinic M5 receptor: a silent or emerging subtype? Br J Pharmacol 2000, 130:13–21.
Eglen RM, Reddy H, Watson N: Selective inactivation of muscarinic receptor subtypes. Int J Biochem 1994, 26:1357–1368.
Fetscher C, Fleichman M, Schmidt M, et al.: M3 muscarinic receptors mediate contraction of human urinary bladder. Br J Pharmacol 2002, 136:641–644.
Bymaster FP, Carter PA, Zhang L, et al.: Investigations into the physiologic role of muscarinic M2 and M4 muscarinic and M4 receptor subtypes using receptor knockout mice. Life Sci 2001, 68:2473–2479.
Saito M, Nakamura I, Miyagawa I: Autoradiographic localization of muscarinic receptors in diabetic rat bladder. Nippon Hinyokika Gakkai Zasshi 1997, 88:858–867.
Nagahama K, Tsujii T, Morita T, et al.: Differences between proximal and distal portions of the male rabbit posterior urethra in the physiologic role of muscarinic cholinergic receptors. Br J Pharmacol 1998, 124:1175–1180.
Chess-Williams R: Muscarinic receptors of the urinary bladder: detrusor, urothelial and prejunctional. Auton Autacoid Pharmacol 2002, 22:133–145.
Watson N, Daniels DV, Ford AD, et al.: Comparative pharmacology of recombinant human M3 and M5 muscarinic receptors expressed in CHO-KI cells. Br J Pharmacol 1999, 127:590–596.
Yamaguchi O, Shishido K, Tamura K, et al.: Evaluation of mRNAs encoding muscarinic receptor subtypes in human detrusor muscle. J Urol 1996, 156:1208–1213.
Wang P, Luthin GR, Ruggieri MR: Muscarinic acetylcholine receptor subtypes mediating urinary bladder contractility and coupling to GTP binding proteins. J Pharmacol Exp Ther 1995, 273:959–966.
Yamanishi T, Yasuda K, Chapple CR, et al.: The role of M2-muscarinic receptors in mediating contraction of the pig urinary bladder in vitro. Br J Pharmacol 2000, 131:1482–1488.
Sigala S, Mirabella G, Peroni A, et al.: Differential gene expression of cholinergic muscarinic receptor subtypes in male and female normal human urinary bladder. Urology 2002, 60:719–725.
Matsui M, Motomura D, Fujikawa T, et al.: Mice lacking M2 and M3 muscarinic acetylcholine receptors are devoid of cholinergic smooth muscle contractions but still viable. J Neurosci 2002, 22:10627–10632.
Ehlert FJ, Sawyer GW, Esqueda EE: Contractile role of M2 and M3 muscarinic receptors in gastrointestinal smooth muscle. Life Sci 1999, 64:387–394.
Stengel PW, Gomeza J, Wess J, et al.: M2 and M4 receptor knockout mice: muscarinic receptor function in cardiac and smooth muscle in vitro. J Pharmacol Exp Ther 2000, 292:877–885.
Yamaguchi O, Shishido K, Tamura K, et al.: Evaluation of mRNAs encoding muscarinic receptor subtypes in human detrusor muscle. J Urol 1996, 156:1208–1213.
Somogyi GT, de Groat WC: Function, signal transduction mechanisms, and plasticity of presynaptic muscarinic receptors in the urinary bladder. Life Sci 1999, 64:411–418.
Yoshimura N, Chancellor MB: Current and future pharmacologic treatment for overactive bladder. J Urol 2002, 168:1897–1913.
Alberts P: Classification of the presynaptic muscarinic receptor subtype that regulates 3H-acetylcholine secretion in the guinea pig urinary bladder in vitro. J Pharmacol Exp Ther 1995, 274:458–468.
Jezior JR, Brady JD, Rosentein DI, et al.: Dependency of detrusor contraction on calcium sensitization and calcium entry through LOE-908-sensitive channels. Br J Pharmacol 2001, 134:78–87.
Chess-Williams R, Chapple CR, Yamanishi T, et al.: The minor population of M3-receptors mediate contraction of human detrusor muscle in vitro. J Auton Pharmacol 2001, 21:243–248.
Hawthorn MH, Chapple CR, Cock M, et al.: Urotheliumderived inhibitory factor(s) influence detrusor muscle contractility in vitro. Br J Pharmacol 2000, 129:416–419.
Templeman L, Chapple CR, Chess-Williams R: Urothelium derived inhibitory factor and cross-talk among receptors of the of the bladder of the pig. J Urol 2002, 167:742–745.
Braverman AS, Tallarida RJ, Ruggieri MR: Interaction between muscarinic receptor subtype signal transduction pathways mediating bladder contraction. Am J Physiol Regul Integr Comp Physiol 2002, 283:R663-R668.
Hedge SS, Choppin A, Bonhaus D, et al.: Functional role of M2 and M3 muscarinic receptors in the urinary bladder of rats in vitro and in vivo. Br J Pharmacol 1997, 120:1409–1418.
Watson GE, Culp DJ: Muscarinic cholinergic receptor subtypes in rat sublingual glands. Am J Physiol 1994, 266:C335-C342.
Culp DJ, Luo W, Richardson LA, et al.: Both M1 and M3 receptors regulate exocrine secretion by mucous acini. Am J Physiol 1996, 271:C1963-C1972.
Tobin G, Giglio D, Gotrick B: Studies of muscarinic receptor subtypes in salivary gland function in anaesthetized rats. Auton Neurosci 2002, 100:1–9.
Seagrave J, Hildebrand R, Johnson LJ: Muscarinic signaling in submandibular salivary acinar cells of ageing rats. Arch Oral Biol 1996, 41:425–430.
Dhein S, Van Koppen CJ, Brodde OE: Muscarinic receptors in the mammalian heart. Pharmacol Res 2001, 44:161–182.
Lucas-Meunier E, Fossier P, Baux G, et al.: Cholinergic modulation of the cortical neuronal network. Pflugers Arch 2003, 446:17–29.
Bymaster FP, McKinzie DL, Felder CC, et al.: Use of M1–M5 muscarinic receptor knockout mice as novel tools to delineate the physiologic roles of the muscarinic cholinergic system. Neurochem Res 2003, 28:437–442.
Ishiura Y, Yoshiyama M, Yokoyama O, et al.: Central muscarinic mechanisms regulating voiding in rats. J Pharmacol Exp Ther 2001, 297:933–939.
Ishizuka O, Bao JG, Yang ZX, et al.: Functional role of central muscarinic receptors for micturition in normal conscious rats. J Urol 2002, 168:2258–2262. The findings of this study suggest that, at least in rats, muscarinic receptors in the central nervous system have a tonic excitatory influence on voiding. Central muscarinic receptors could be an important target for treatment.
Bradin AF: A myogenic basis for the overactive bladder. Urology 1997, 50(suppl A):57–67.
Charlton RG, Morley AR, Chambers P, et al.: Focal changes in nerve, muscle, and connective tissue in normal and unstable human bladder. BJU Int 1999, 84:953–960.
Mills IW, Greenland JE, McMurray G, et al.: Studies of the pathophysiology of idiopathic detrusor instability: the physiologic properties of the detrusor smooth muscle and its pattern of innervation. J Urol 2000, 163:646–651.
Somogyi GT, de Groat WC: Evidence for inhibitory nicotinic and facilitatory muscarinic receptors in cholinergic nerve terminals of the rat urinary bladder. J Auton Nerv Syst 1992, 37:89–98.
Somogyi GT, Tanowitz M, de Groat WC: M1 muscarinic receptor-mediated facilitation of acetylcholine release in the rat urinary bladder. J Physiol 1994, 480:81–89.
Somogyi GT, Zernova GV, Yoshiyama M, et al.: Frequency dependence of muscarinic facilitation of transmitter release in urinary bladder strips from neurally intact or chronic spinal cord transected rats. Br J Pharmacol 1998, 125:241–246.
Somogyi GT, Zernova GV, Yoshiyama M, et al.: Change in muscarinic modulation of transmitter release in the rat urinary bladder after spinal cord injury. Neurochem Int 2003, 43:73–77.
Braverman AS, Luthin GR, Ruggieri MR: M2 muscarinic receptor contributes to contraction of the denervated rat urinary bladder. Am J Physiol 1998, 275:R1654-R1660. This study demonstrates that, in spinal injury, the M2 receptor may have an active role in micturition, which may have implications for antimuscarinic treatment.
Ekstrom J, Malmberg L: Development of supersensitivity to methacholine in the rat detrusor following either parasympathetic denervation or decentralization. Acta Physiol Scand 1984, 122:175–179.
Nilvebrant L, Ekstrom J, Malmberg L: Muscarinic receptor density in the rat urinary bladder after denervation, hypertrophy, and urinary diversion. Acta Pharmacol Toxicol 1986, 59:306–314.
Bayliss M, Wu C, Newgreen D, et al.: A quantitative study of atropine-resistant contractile responses in human detrusor smooth muscle, from stable, unstable and obstructed bladders. J Urol 1999, 162:1833–1839.
Waring JV, Wendt JR: Effects of streptozotocin-induced diabetes mellitus on intracellular calcium and contraction of longitudinal smooth muscle from rat urinary bladder. J Urol 2000, 163:323–330.
Yoshida M, Inadome A, Murakami S, et al.: Effects of age and muscle stretching on acetylcholine release in isolated human bladder smooth muscle (Abstract 160). J Urol 2002, 167:40.
Tong YC, Chin WT, Cheng JT: Alterations in urinary bladder M2-muscarinic receptor protein and mRNA in 2-week streptozotocin-induced diabetic rats. Neurosci Lett 1997, 277:173–176.
Watanabe M, Yamagishi WH, Kawaguchi M: Lowered susceptibility of muscarinic receptor involved in salivary secretion of streptozotocin-induced diabetic rats. Jpn J Pharmacol 2001, 87:117–124.
Oki T, Yamada S, Tohma A, et al.: Characteristics in rat tissues after oral administration of oxybutynin and propiverine. Biol Pharm Bull 2001, 24:491–495.
Nilvebrant L, Andersson KE, Gillberg PG, et al.: Tolterodine: a new bladder-selective antimuscarinic agent. Eur J Pharmacol 1997, 327:195–207.
Wallis RM, Napier CM: Muscarinic antagonists in development for disorders of smooth muscle function. Life Sci 1999, 64:395–401.
Gillberg PG, Sundquist S, Nilvebrandt L: Comparison of the in vitro and in vivo profiles of tolterodine with those of subtype-selective muscarinic receptor antagonists. Eur J Pharmacol 1998, 349:285–292.
Yamanashi T, Chapple CR, Chess-Williams R: Which muscarinic receptor is important in the bladder? World J Urol 2001, 19:299–306.
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Scarpero, H.M., Dmochowski, R.R. Muscarinic receptors: What we know. Curr Urol Rep 4, 421–428 (2003). https://doi.org/10.1007/s11934-003-0021-3
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DOI: https://doi.org/10.1007/s11934-003-0021-3