Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and beta-adrenoceptors.
The normal physiological contraction of the urinary bladder, which is required for voiding, is predominantly mediated by muscarinic receptors, primarily the M3 subtype, with the M2 subtype providing a secondary backup role. Bladder relaxation, which is required for urine storage, is mediated by beta-adrenoceptors, in most species involving a strong beta3-component. An excessive stimulation of contraction or a reduced relaxation of the detrusor smooth muscle during the storage phase of the micturition cycle may contribute to bladder dysfunction known as the overactive bladder. Therefore, interference with the signal transduction of these receptors may be a viable approach to develop drugs for the treatment of overactive bladder. The prototypical signaling pathway of M3 receptors is activation of phospholipase C (PLC), and this pathway is also activated in the bladder. Nevertheless, PLC apparently contributes only in a very minor way to bladder contraction. Rather, muscarinic-receptor-mediated bladder contraction involves voltage-operated Ca2+ channels and Rho kinase. The prototypical signaling pathway of beta-adrenoceptors is an activation of adenylyl cyclase with the subsequent formation of cAMP. Nevertheless, cAMP apparently contributes in a minor way only to beta-adrenoceptor-mediated bladder relaxation. BKCa channels may play a greater role in beta-adrenoceptor-mediated bladder relaxation. We conclude that apart from muscarinic receptor antagonists and beta-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive bladder.
Department of Pharmacology and Pharmacotherapy, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.
Elfaridah P
EP
Frazier
Stephan L M
SL
Peters
Alan S
AS
Braverman
Michael R
MR
Ruggieri
Martin C
MC
Michel
D000318:Adrenergic beta-Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D006801:Humans; D018727:Muscarinic Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D001743:Urinary Bladder / Q000378:metabolism* / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy / Q000503:physiopathology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000318:Adrenergic beta-Agonists; D018727:Muscarinic Antagonists; D015221:Potassium Channels; D047428:Protein Kinase Inhibitors; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D054460:rho-Associated Kinases