rottlerin

Rottlerin has been shown to be an uncoupler of mitochondrial oxidative phosphorylation.{{cite journal | vauthors = Soltoff SP | title = Rottlerin is a mitochondrial uncoupler that decreases cellular ATP levels and indirectly blocks protein kinase Cdelta tyrosine phosphorylation | journal = The Journal of Biological Chemistry | volume = 276 | issue = 41 | pages = 37986–37992 | date = October 2001 | pmid = 11498535 | doi = 10.1074/jbc.M105073200 | doi-access = free }}{{cite journal | vauthors = Kayali AG, Austin DA, Webster NJ | title = Rottlerin inhibits insulin-stimulated glucose transport in 3T3-L1 adipocytes by uncoupling mitochondrial oxidative phosphorylation | journal = Endocrinology | volume = 143 | issue = 10 | pages = 3884–3896 | date = October 2002 | pmid = 12239100 | doi = 10.1210/en.2002-220259 | doi-access = free }}{{cite journal | vauthors = Tillman DM, Izeradjene K, Szucs KS, Douglas L, Houghton JA | title = Rottlerin sensitizes colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via uncoupling of the mitochondria independent of protein kinase C | journal = Cancer Research | volume = 63 | issue = 16 | pages = 5118–5125 | date = August 2003 | pmid = 12941843 }}

Rottlerin is a potent large conductance potassium channel (BKCa++) opener.{{cite journal | vauthors = Clements RT, Cordeiro B, Feng J, Bianchi C, Sellke FW | title = Rottlerin increases cardiac contractile performance and coronary perfusion through BKCa++ channel activation after cold cardioplegic arrest in isolated hearts | journal = Circulation | volume = 124 | issue = 11 Suppl | pages = S55–S61 | date = September 2011 | pmid = 21911819 | pmc = 3358121 | doi = 10.1161/CIRCULATIONAHA.110.012112 }} BKCa++ is found in the inner mitochondrial membrane of cardiomyocytes.{{cite journal | vauthors = Zakharov SI, Morrow JP, Liu G, Yang L, Marx SO | title = Activation of the BK (SLO1) potassium channel by mallotoxin | journal = The Journal of Biological Chemistry | volume = 280 | issue = 35 | pages = 30882–30887 | date = September 2005 | pmid = 15998639 | doi = 10.1074/jbc.M505302200 | doi-access = free }} Opening these channels is beneficial for post-ischemic changes in vasodilation.{{cite journal | vauthors = Han JG, Yang Q, Yao XQ, Kwan YW, Shen B, He GW | title = Role of large-conductance calcium-activated potassium channels of coronary arteries in heart preservation | journal = The Journal of Heart and Lung Transplantation | volume = 28 | issue = 10 | pages = 1094–1101 | date = October 2009 | pmid = 19782293 | doi = 10.1016/j.healun.2009.06.011 }} Other BKCa++ channel openers are reported to limit the mitochondrial calcium overload due to ischemia.{{cite journal | vauthors = Kang SH, Park WS, Kim N, Youm JB, Warda M, Ko JH, Ko EA, Han J | display-authors = 6 | title = Mitochondrial Ca2+-activated K+ channels more efficiently reduce mitochondrial Ca2+ overload in rat ventricular myocytes | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 293 | issue = 1 | pages = H307–H313 | date = July 2007 | pmid = 17351070 | doi = 10.1152/ajpheart.00789.2006 }}{{cite journal | vauthors = Sato T, Saito T, Saegusa N, Nakaya H | title = Mitochondrial Ca2+-activated K+ channels in cardiac myocytes: a mechanism of the cardioprotective effect and modulation by protein kinase A | journal = Circulation | volume = 111 | issue = 2 | pages = 198–203 | date = January 2005 | pmid = 15623543 | doi = 10.1161/01.cir.0000151099.15706.b1 | s2cid = 9912508 | doi-access = }} Rottlerin is also capable of reducing oxygen radical formation.

Other BKCa++ channel openers (NS1619, NS11021 and DiCl-DHAA) have been reported to have cardio-protective effects after ischemic-reperfusion injury.{{cite journal | vauthors = Bentzen BH, Osadchii O, Jespersen T, Hansen RS, Olesen SP, Grunnet M | title = Activation of big conductance Ca(2+)-activated K (+) channels (BK) protects the heart against ischemia-reperfusion injury | journal = Pflügers Archiv | volume = 457 | issue = 5 | pages = 979–988 | date = March 2009 | pmid = 18762970 | doi = 10.1007/s00424-008-0583-5 | s2cid = 25090971 }}{{cite journal | vauthors = Sakamoto K, Ohya S, Muraki K, Imaizumi Y | title = A novel opener of large-conductance Ca2+ -activated K+ (BK) channel reduces ischemic injury in rat cardiac myocytes by activating mitochondrial K(Ca) channel | journal = Journal of Pharmacological Sciences | volume = 108 | issue = 1 | pages = 135–139 | date = September 2008 | pmid = 18758135 | doi = 10.1254/jphs.08150sc | doi-access = free }} There were reductions in mitochondrial Ca++ overload, mitochondrial depolarization, increased cell viability and improved function in the whole heart.

Mallotoxin is also a hERG potassium channel activator.{{cite journal | vauthors = Zeng H, Lozinskaya IM, Lin Z, Willette RN, Brooks DP, Xu X | title = Mallotoxin is a novel human ether-a-go-go-related gene (hERG) potassium channel activator | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 319 | issue = 2 | pages = 957–962 | date = November 2006 | pmid = 16928897 | doi = 10.1124/jpet.106.110593 | s2cid = 21096055 }}

Clements et al. reported that rottlerin improves the recovery of isolated rat hearts perfused with buffer after cold cardioplegic arrest. A majority of patients recover but some develop a cardiac low-output syndrome attributable in part to depressed left ventricular or atrial contractility, which increases chance of death.

Rottlerin increases in isolated heart contractility independent of its vascular effects, as well as enhanced perfusion through vasomotor activity. The activation of BKCa++ channels by rottlerin relaxes coronary smooth muscle and improves myocardial perfusion after cardioplegia.

Myocardial stunning is associated with oxidant radical damage and calcium overload. Contractile abnormalities can occur through oxidant-dependent damage and also through calcium overload in the mitochondria resulting in mitochondrial damage.{{cite journal | vauthors = Bolli R, Marbán E | title = Molecular and cellular mechanisms of myocardial stunning | journal = Physiological Reviews | volume = 79 | issue = 2 | pages = 609–634 | date = April 1999 | pmid = 10221990 | doi = 10.1152/physrev.1999.79.2.609 | s2cid = 18283833 }}{{cite journal | vauthors = Kloner RA, Jennings RB | title = Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 2 | journal = Circulation | volume = 104 | issue = 25 | pages = 3158–3167 | date = December 2001 | pmid = 11748117 | doi = 10.1161/hc5001.100039 | s2cid = 52874593 | doi-access = }}{{cite journal | vauthors = Kloner RA, Jennings RB | title = Consequences of brief ischemia: stunning, preconditioning, and their clinical implications: part 1 | journal = Circulation | volume = 104 | issue = 24 | pages = 2981–2989 | date = December 2001 | pmid = 11739316 | doi = 10.1161/hc4801.100038 | doi-access = free }} BKCa++ channels reside in the inner mitochondrial membrane and their activation is proposed to increase K+ accumulation in mitochondria. This limits {{chem|Ca|2+}} influx into mitochondria, reducing mitochondrial depolarization and permeability transition pore opening. This may result in less mitochondrial damage and therefore greater contractility since there is a decrease in apoptosis compared to no stimulation of BKCa++ channels.

Rottlerin also enhances the cardioplegia-induced phosphorylation of Akt on the activation residue Thr308. Akt activation modulates mitochondrial depolarization and the permeability transition pore.{{cite journal | vauthors = Miura T, Tanno M, Sato T | title = Mitochondrial kinase signalling pathways in myocardial protection from ischaemia/reperfusion-induced necrosis | journal = Cardiovascular Research | volume = 88 | issue = 1 | pages = 7–15 | date = October 2010 | pmid = 20562423 | doi = 10.1093/cvr/cvq206 | doi-access = free }}{{cite journal | vauthors = Halestrap AP, Clarke SJ, Khaliulin I | title = The role of mitochondria in protection of the heart by preconditioning | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1767 | issue = 8 | pages = 1007–1031 | date = August 2007 | pmid = 17631856 | pmc = 2212780 | doi = 10.1016/j.bbabio.2007.05.008 }} Clements et al. found that Akt functions downstream of the BKCa++ channels and its activation is considered beneficial after ischemic-reperfusion injury. It is unclear what the specific role of Akt may play in modulating of myocardial function after rottlerin treatment of cardioplegia. More research needs to be done to examine if Akt is necessary to improve cardiac function when rottlerin is administered.

The antioxidant properties of rottlerin have been demonstrated but it is unclear whether the effects are because of BKCa++ channel opening or an additional mechanism of rottlerin.{{cite journal | vauthors = Heinen A, Aldakkak M, Stowe DF, Rhodes SS, Riess ML, Varadarajan SG, Camara AK | title = Reverse electron flow-induced ROS production is attenuated by activation of mitochondrial Ca2+-sensitive K+ channels | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 293 | issue = 3 | pages = H1400–H1407 | date = September 2007 | pmid = 17513497 | doi = 10.1152/ajpheart.00198.2007 | s2cid = 20330939 }} There was no oxygen dependent damage found by rottlerin in the study conducted by Clements et al.

Rottlerin has been reported to be a PKCδ inhibitor.{{cite journal | vauthors = Gschwendt M, Müller HJ, Kielbassa K, Zang R, Kittstein W, Rincke G, Marks F | title = Rottlerin, a novel protein kinase inhibitor | journal = Biochemical and Biophysical Research Communications | volume = 199 | issue = 1 | pages = 93–98 | date = February 1994 | pmid = 8123051 | doi = 10.1006/bbrc.1994.1199 }} PKCδ has been implicated in depressing cardiac function and cell death after ischemia-reperfusion injury as well as promoting vascular smooth muscle contraction and decreasing perfusion. However, the role of rottlerin as a specific PKCδ inhibitor has been questioned. There have been several studies using rottlerin as a PKCδ selective inhibitor based on in vitro studies, but some studies showed it did not block PKCδ activity and did block other kinase and non-kinase proteins in vitro.{{cite journal | vauthors = Davies SP, Reddy H, Caivano M, Cohen P | title = Specificity and mechanism of action of some commonly used protein kinase inhibitors | journal = The Biochemical Journal | volume = 351 | issue = Pt 1 | pages = 95–105 | date = October 2000 | pmid = 10998351 | pmc = 1221339 | doi = 10.1042/0264-6021:3510095 }}{{cite journal | vauthors = Soltoff SP | title = Rottlerin is a mitochondrial uncoupler that decreases cellular ATP levels and indirectly blocks protein kinase Cdelta tyrosine phosphorylation | journal = The Journal of Biological Chemistry | volume = 276 | issue = 41 | pages = 37986–37992 | date = October 2001 | pmid = 11498535 | doi = 10.1074/jbc.M105073200 | doi-access = free }} Rottlerin also uncouples mitochondria at high doses and results in depolarization of the mitochondrial membrane potential. It was found to reduce ATP levels, activate 5'-AMP-activated protein kinase and affect mitochondrial production of reactive oxygen species (ROS).{{cite journal | vauthors = Tapia JA, Jensen RT, García-Marín LJ | title = Rottlerin inhibits stimulated enzymatic secretion and several intracellular signaling transduction pathways in pancreatic acinar cells by a non-PKC-delta-dependent mechanism | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1763 | issue = 1 | pages = 25–38 | date = January 2006 | pmid = 16364465 | doi = 10.1016/j.bbamcr.2005.10.007 | doi-access = }} It is difficult to say that rottlerin is a selective inhibitor of PKCδ since there are biological and biochemical processes that are PKCδ –independent that may affect outcomes. A proposed mechanism of why rottlerin was found to inhibit PKCδ is that it decreased ATP levels and can block PKCδ tyrosine phosphorylation and activation.

The Kamala tree, also known as Mallotus philippensis, grows in Southeast Asia. The fruit of this tree is covered with a red powder called kamala, and is used locally to make dye for textiles, syrup and used as an old remedy for tape-worm, because it has a laxative effect.{{cite journal | vauthors = Rao VS, Seshadri TR | year = 1947 | title = Kamala dye as an anthelmintic | journal = Proceedings of the Indian Academy of Sciences | volume = 26 | issue = 3| pages = 178–181 | doi = 10.1007/BF03170871 | s2cid = 81455004 }} Other uses include afflictions with the skin, eye diseases, bronchitis, abdominal disease, and spleen enlargement but scientific evidence is not present.{{cite journal | vauthors = Mitra R, Kapoor LD | title = Kamala--the national flower of India--its ancient history and uses in Indian medicine | journal = Indian Journal of History of Science | volume = 11 | issue = 2 | pages = 125–132 | date = November 1976 | pmid = 11610202 }}

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{{Channel openers}}

Category:Phloroglucinols

Category:HERG activator

Category:Potassium channel openers

Category:Plant toxins