title: Roscovitine inhibits CaV3.1 (T-type) channels by preferentially affecting closed-state inactivation.
abstract: T-type calcium channels (Ca(V)3) play an important role in many physiological and pathological processes, including cancerogenesis. Ca(V)3 channel blockers have been proposed as potential cancer treatments. Roscovitine, a trisubstituted purine, is a cyclin-dependent kinase (CDK) inhibitor that is currently undergoing phase II clinical trials as an anticancer drug and has been shown to affect calcium and potassium channel activity. Here, we investigate the effect of roscovitine on Ca(V)3.1 channels. Ca(V)3.1 channels were transiently expressed in human embryonic kidney 293 cells, and currents were recorded by using the whole-cell patch-clamp technique. Roscovitine blocks Ca(V)3.1 channels with higher affinity for depolarized cells (EC₅₀ of 10 μM), which is associated with a negative shift in the voltage dependence of closed-state inactivation. Enhanced inactivation is mediated by roscovitine-induced acceleration of closed-state inactivation and slowed recovery from inactivation. Small effects of roscovitine were also observed on T-channel deactivation and open-state inactivation, but neither could explain the inhibitory effect. Roscovitine inhibits Ca(V)3.1 channels within the therapeutic range (10-50 μM) in part by stabilizing the closed-inactivated state. The ability of roscovitine to block multiple mediators of proliferation, including CDKs and Ca(V)3.1 channels, may facilitate its anticancer properties.
authors.affiliation: Department of Pharmacology and Physiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. viktor_yarotskyy@urmc.rochester.edu
authors.forename: Viktor
authors.initials: V
authors.lastname: Yarotskyy
authors.forename: Keith S
authors.initials: KS
authors.lastname: Elmslie
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D055724:Electrophysiological Phenomena / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology; D007700:Kinetics; D008564:Membrane Potentials / Q000502:physiology; D011687:Purines / Q000494:pharmacology*; D051381:Rats; D000077546:Roscovitine; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; C500994:Cacna1g protein, rat; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D011687:Purines; D000077546:Roscovitine
references.citation: Physiology (Bethesda). 2004 Oct;19:285-92
references.pmid: 15381757
references.citation: J Neurophysiol. 1992 Jul;68(1):213-32
references.pmid: 1325546
references.citation: Neuropharmacology. 2007 Mar;52(3):883-94
references.pmid: 17125805
references.citation: Leukemia. 2004 Apr;18(4):747-55
references.pmid: 14973497
references.citation: Eur J Neurosci. 2006 Jun;23(12):3200-8
references.pmid: 16820010
references.citation: Mol Pharmacol. 1998 Dec;54(6):1080-7
references.pmid: 9855637
references.citation: Nature. 2011 Mar 10;471(7337):230-4
references.pmid: 21307850
references.citation: Br J Cancer. 2005 Oct 3;93(7):781-92
references.pmid: 16175187
references.citation: Neuron. 1989 Aug;3(2):153-61
references.pmid: 2560389
references.citation: Eur J Biochem. 1997 Jan 15;243(1-2):518-26
references.pmid: 9030780
references.citation: J Biol Chem. 2010 Jan 1;285(1):43-53
references.pmid: 19887376
references.citation: Mol Syst Biol. 2008;4:228
references.pmid: 18985027
references.citation: Novartis Found Symp. 2005;266:225-32; discussion 232-4
references.pmid: 16050271
references.citation: Biophys J. 1981 Mar;33(3):323-51
references.pmid: 6261850
references.citation: Cancer Invest. 2011 Jun;29(5):339-46
references.pmid: 21438841
references.citation: J Neurophysiol. 2008 Jun;99(6):3151-6
references.pmid: 18417624
references.citation: Cell Calcium. 2006 Aug;40(2):115-20
references.pmid: 16806465
references.citation: Br J Pharmacol. 2007 Oct;152(3):386-95
references.pmid: 17700718
references.citation: J Cell Biochem. 2007 Mar 1;100(4):865-74
references.pmid: 17203463
references.citation: Am J Physiol Cell Physiol. 2009 Apr;296(4):C701-10
references.pmid: 19244476
references.citation: World J Gastroenterol. 2008 Aug 28;14(32):4984-91
references.pmid: 18763278
references.citation: Nat Chem Biol. 2008 Nov;4(11):682-90
references.pmid: 18936753
references.citation: Pharmacol Res. 2008 Mar;57(3):181-95
references.pmid: 18329284
references.citation: Cell. 2008 May 2;133(3):387-91
references.pmid: 18455976
references.citation: J Physiol. 2009 Feb 1;587(3):551-65
references.pmid: 19074970
references.citation: Br J Cancer. 2007 Jan 15;96(1):29-37
references.pmid: 17179992
references.citation: Cell Calcium. 2008 Jan;43(1):49-58
references.pmid: 17532042
references.citation: Eur J Biochem. 1997 Jan 15;243(1-2):527-36
references.pmid: 9030781
references.citation: Biophys J. 2005 Sep;89(3):1681-91
references.pmid: 15951378
references.citation: Pharmacol Rev. 2005 Dec;57(4):411-25
references.pmid: 16382099
references.citation: J Pharmacol Exp Ther. 2000 Oct;295(1):302-8
references.pmid: 10991994
references.citation: J Membr Biol. 2005 Jun;205(3):115-24
references.pmid: 16362499
references.citation: J Gen Physiol. 1999 Aug;114(2):185-201
references.pmid: 10435997
references.citation: Diabetes. 2000 Jan;49(1):59-64
references.pmid: 10615950
references.citation: Proc Natl Acad Sci U S A. 1982 Apr;79(7):2415-9
references.pmid: 6954549
references.citation: Bioorg Med Chem Lett. 2006 Oct 1;16(19):5014-7
references.pmid: 16876410
references.citation: Bioorg Med Chem Lett. 2008 Jul 15;18(14):3899-901
references.pmid: 18585035
references.citation: J Neurochem. 2008 May;105(4):1450-61
references.pmid: 18221369
references.citation: J Clin Invest. 2009 Jun;119(6):1659-67
references.pmid: 19451696
references.citation: Cancer Lett. 2008 Aug 18;267(1):116-24
references.pmid: 18455293
references.citation: Blood. 2007 Aug 15;110(4):1238-50
references.pmid: 17420287
references.citation: Expert Opin Investig Drugs. 2003 Jun;12(6):955-70
references.pmid: 12783600
references.citation: Neuropharmacology. 2010 Jul-Aug;59(1-2):58-69
references.pmid: 20363234
references.citation: J Physiol. 1986 Jul;376:341-57
references.pmid: 2432232
references.citation: J Neurosci Res. 2004 Mar 15;75(6):733-41
references.pmid: 14994334
references.citation: Physiol Rev. 2003 Jan;83(1):117-61
references.pmid: 12506128
references.citation: Oncol Rep. 2009 Nov;22(5):1229-35
references.pmid: 19787244