title: Kv1.3 inhibitors have differential effects on glucose uptake and AMPK activity in skeletal muscle cell lines and mouse ex vivo skeletal muscle.
abstract: Knockout of Kv1.3 improves glucose homeostasis and confers resistance to obesity. Additionally, Kv1.3 inhibition enhances glucose uptake. This is thought to occur through calcium release. Kv1.3 inhibition in T-lymphocytes alters mitochondrial membrane potential, and, as many agents that induce Ca(2+) release or inhibit mitochondrial function activate AMPK, we hypothesised that Kv1.3 inhibition would activate AMPK and increase glucose uptake. We screened cultured muscle with a range of Kv1.3 inhibitors for their ability to alter glucose uptake. Only Psora4 increased glucose uptake in C2C12 myotubes. None of the inhibitors had any impact on L6 myotubes. Magratoxin activated AMPK in C2C12 myotubes and only Pap1 activated AMPK in the SOL. Kv1.3 inhibitors did not alter cellular respiration, indicating a lack of effect on mitochondrial function. In conclusion, AMPK does not mediate the effects of Kv1.3 inhibitors and they display differential effects in different skeletal muscle cell lines without impairing mitochondrial function.
authors.affiliation: Division of Cardiovascular and Diabetes Medicine, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, d.l.hamilton@stir.ac.uk.
authors.forename: D Lee
authors.initials: DL
authors.lastname: Hamilton
authors.forename: Craig
authors.initials: C
authors.lastname: Beall
authors.forename: Stewart
authors.initials: S
authors.lastname: Jeromson
authors.forename: Cyrille
authors.initials: C
authors.lastname: Chevtzoff
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cuthbertson
authors.forename: Michael L J
authors.initials: ML
authors.lastname: Ashford
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D005363:Ficusin / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D066298:In Vitro Techniques; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D051379:Mice; D008931:Mitochondria, Muscle / Q000187:drug effects; D023421:Models, Animal; D018485:Muscle Fibers, Skeletal / Q000187:drug effects; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000073718:Pancreatitis-Associated Proteins; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D051381:Rats; D012604:Scorpion Venoms / Q000494:pharmacology
chemical_list: C499898:5-(4-phenylbutoxy)psoralen; D051664:Kv1.3 Potassium Channel; D000073718:Pancreatitis-Associated Proteins; D026902:Potassium Channel Blockers; C000612141:REG3A protein, human; D012604:Scorpion Venoms; C077910:margatoxin; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D005363:Ficusin; D002118:Calcium
references.citation: Am J Physiol Cell Physiol. 2006 Feb;290(2):C345-51
references.pmid: 16403947
references.citation: Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):1251-9
references.pmid: 20114030
references.citation: Immunol Rev. 2009 Sep;231(1):59-87
references.pmid: 19754890
references.citation: Am J Physiol. 1998 Dec;275(6):C1487-97
references.pmid: 9843710
references.citation: Am J Physiol Endocrinol Metab. 2006 Jun;290(6):E1276-86
references.pmid: 16418206
references.citation: Endocr J. 2006 Jun;53(3):267-93
references.pmid: 16702775
references.citation: Free Radic Biol Med. 2011 Mar 1;50(5):567-75
references.pmid: 21163346
references.citation: J Clin Endocrinol Metab. 2006 Feb;91(2):654-8
references.pmid: 16317062
references.citation: Acta Physiol Scand. 2002 Dec;176(4):283-92
references.pmid: 12444934
references.citation: Am J Physiol. 1991 Mar;260(3 Pt 1):C555-61
references.pmid: 2003578
references.citation: Hum Mol Genet. 2003 Mar 1;12(5):551-9
references.pmid: 12588802
references.citation: Am J Physiol Endocrinol Metab. 2010 May;298(5):E1058-71
references.pmid: 20159855
references.citation: Am J Physiol. 1984 Sep;247(3 Pt 1):E297-304
references.pmid: 6433719
references.citation: Biochem Cell Biol. 1990 Feb;68(2):536-42
references.pmid: 2188683
references.citation: Appl Physiol Nutr Metab. 2009 Jun;34(3):481-7
references.pmid: 19448718
references.citation: Int J Obes (Lond). 2008 Aug;32(8):1222-32
references.pmid: 18542083
references.citation: J Physiol. 2008 Mar 15;586(6):1731-41
references.pmid: 18202101
references.citation: Int J Sports Med. 2008 Oct;29(10):785-94
references.pmid: 18401805
references.citation: Acta Physiol (Oxf). 2009 May;196(1):115-27
references.pmid: 19245657
references.citation: Am J Physiol Cell Physiol. 2010 Aug;299(2):C240-50
references.pmid: 20410436
references.citation: J Neurophysiol. 2000 Apr;83(4):2332-48
references.pmid: 10758137
references.citation: Nat Rev Mol Cell Biol. 2002 Apr;3(4):267-77
references.pmid: 11994746
references.citation: Am J Physiol Endocrinol Metab. 2011 Aug;301(2):E380-90
references.pmid: 21586699
references.citation: Endocrinology. 1992 May;130(5):2535-44
references.pmid: 1572281
references.citation: BMC Cell Biol. 2010 May 27;11:37
references.pmid: 20507574
references.citation: Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E286-92
references.pmid: 17405829
references.citation: FEBS Lett. 1998 May 8;427(2):193-7
references.pmid: 9607310
references.citation: Nature. 1988 May 12;333(6169):183-5
references.pmid: 3285221
references.citation: PLoS One. 2008 May 07;3(5):e2102
references.pmid: 18461163
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3112-7
references.pmid: 14981264
references.citation: Am J Physiol Endocrinol Metab. 2008 Jul;295(1):E29-37
references.pmid: 18477703
references.citation: J Biol Chem. 2002 Apr 12;277(15):13268-80
references.pmid: 11812778
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 30;105(39):14861-6
references.pmid: 18818304