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Pathway Description
Mirabegron Action Pathway
Homo sapiens
Drug Action Pathway
Mirabegron is a beta-3 adrenergic receptor agonist that is used to treat overactive bladder and neurogenic detrusor activity. It relaxes the smooth muscle of the bladder which expands the bladder to relieve urgency. It is an oral medication that lacks significant antimuscarinic activity to reduce adverse effects in comparison to other drugs used for overactive bladder treatment. Mirabegron can be found under the brand name Myrbetriq and allows for the relaxation of detrusor smooth muscle of the bladder during the storage phase of the urinary bladder fill-void cycle via the activation of adenylyl cyclase. Once Mirabegron is administered and it binds to the beta-3 adrenergic receptor, the G protein signalling cascade begins. The alpha and beta/gamma subunits of the G protein separate and GDP is replaced with GTP on the alpha subunit. This alpha subunit then activates adenylyl cyclase which converts ATP to cAMP. cAMP then activates protein kinase A (PKA) which in turn phosphorylates targets and inhibits MLCK through decreased calcium levels causing muscle relaxation. PKA can phosphorylate certain Gq-coupled receptors as well as phospholipase C (PLC) and thereby inhibit G protein-coupled receptor (GPCR) -PLC-mediated phosphoinositide (PI) generation, and thus calcium flux. PKA phosphorylates the inositol 1,4,5-trisphosphate (IP3) receptor to reduce its affinity for IP3 and further limit calcium mobilization. PKA phosphorylates myosin light chain kinase (MLCK) and decreases its affinity to calcium calmodulin, thus reducing activity and myosin light chain (MLC) phosphorylation. PKA also phosphorylates KCa++ channels in ASM, increasing their open-state probability (and therefore K+ efflux) and promoting hyperpolarization. Since myosine light chain kinase is not activated, Serine/threonine-protein phosphatase continues to dephosphorylate myosin LC-P, and more cannot be synthesized so myosin remains unbound from actin causing muscle relaxation. This relaxation of the smooth muscles in the bladder causes the bladder to expand to relax, making the sense of urgency for urination lesser. Some side effects of using mirabegron may include nausea, constipation, headache, and dizziness.
References
Mirabegron Pathway References
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
Pubmed: 29126136
Billington CK, Penn RB: Signaling and regulation of G protein-coupled receptors in airway smooth muscle. Respir Res. 2003;4(1):2. Epub 2003 Mar 14.
Pubmed: 12648290
Andersson KE: Prospective pharmacologic therapies for the overactive bladder. Ther Adv Urol. 2009 Jun;1(2):71-83. doi: 10.1177/1756287209103937.
Pubmed: 21789056
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