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Pathway Description
Timolol Action Pathway
Homo sapiens
Drug Action Pathway
Timolol is a beta blocker medication, making it part of the antihypertensive drug class. It relieves symptoms such as tachycardia, vascular headaches, hypertension, angina and tremors. Timolol, much like propranolol or oxprenolol, begins its journey by inhibiting the beta-1 adrenergic receptors in the heart. Entering the myocyte, this activates a G-protein signalling cascade, which activates cAMP -dependent protein kinase type 1-alpha regulatory subunit. From there, cAMP-dependent protein kinase catalytic subunit alpha activates outage-dependent L-type calcium channel subunit alpha 1C and 2 other transports which bring calcium into the myocyte from outside of the cell. cAMP-dependent protein kinase catalytic subunit alpha is activated through ryanodine receptor 2, which is also transporting calcium into the myocyte from the the sarcoplasmic reticulum. The calcium and calmodulin then activate myosin light chain kinase, which is located in the smooth vascular muscle. This, paired with the calcium activating a series of troponin enzymes that activate tropomyosin enzymes in the striated muscle, results in a muscle contraction. Then in the cell membrane we have PIP2(16:0/20:3(8Z,11Z,14Z)) catalyzing into DG(14:0/14:1(9Z)/0:0) and inositol 1,4,5-triphosphate with the help of the enzyme 1-phosphatidylinositol 4,5-biphosphate phosphodiesterase beta-1. This enzyme is activated through the G-protein signalling cascade, which stems from the type-1 angiotensin II receptor. Around the cell there are many transports happening through many different transporters, leading in and out of the cell Some of the transports into the cell include sodium and calcium, while transports are also working hard to constantly export potassium from the cell. Returning to the sarcoplasmic reticulum, cardiac phospholamban inhibits the transporter sarcoplasmic/endoplasmic reticulum calcium ATPase 2, which sees water and ATP catalyzed through it to become phosphorus and ADP, while transporting calcium into the sarcoplasmic reticulum.
References
Timolol Pathway References
Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5.
Pubmed: 11752352
Nieminen T, Uusitalo H, Maenpaa J, Turjanmaa V, Rane A, Lundgren S, Ropo A, Rontu R, Lehtimaki T, Kahonen M: Polymorphisms of genes CYP2D6, ADRB1 and GNAS1 in pharmacokinetics and systemic effects of ophthalmic timolol. A pilot study. Eur J Clin Pharmacol. 2005 Dec;61(11):811-9. doi: 10.1007/s00228-005-0052-4. Epub 2005 Nov 17.
Pubmed: 16315032
Varma DR, Shen H, Deng XF, Peri KG, Chemtob S, Mulay S: Inverse agonist activities of beta-adrenoceptor antagonists in rat myocardium. Br J Pharmacol. 1999 Jun;127(4):895-902. doi: 10.1038/sj.bjp.0702616.
Pubmed: 10433496
Hirooka K, Kelly ME, Baldridge WH, Barnes S: Suppressive actions of betaxolol on ionic currents in retinal ganglion cells may explain its neuroprotective effects. Exp Eye Res. 2000 May;70(5):611-21. doi: 10.1006/exer.2000.0822.
Pubmed: 10870519
Bhattacharyya BJ, Lee E, Krupin D, Hockberger P, Krupin T: (-)-Isoproterenol modulation of maxi-K(+) channel in nonpigmented ciliary epithelial cells through a G-protein gated pathway. Curr Eye Res. 2002 Mar;24(3):173-81.
Pubmed: 12221524
Wang T, Kaumann AJ, Brown MJ: (--)-Timolol is a more potent antagonist of the positive inotropic effects of (--)-adrenaline than of those of (--)-noradrenaline in human atrium. Br J Clin Pharmacol. 1996 Aug;42(2):217-23.
Pubmed: 8864321
Striated Muscle Contraction References
Cooke R: The sliding filament model: 1972-2004. J Gen Physiol. 2004 Jun;123(6):643-56. doi: 10.1085/jgp.200409089.
Pubmed: 15173218
Szent-Gyorgyi A: The mechanism of muscle contraction. Proc Natl Acad Sci U S A. 1974 Sep;71(9):3343-4.
Pubmed: 4610574
Kuo IY, Ehrlich BE: Signaling in muscle contraction. Cold Spring Harb Perspect Biol. 2015 Feb 2;7(2):a006023. doi: 10.1101/cshperspect.a006023.
Pubmed: 25646377
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