title: Characterization of Erg K+ channels in alpha- and beta-cells of mouse and human islets.
abstract: Voltage-gated eag-related gene (Erg) K(+) channels regulate the electrical activity of many cell types. Data regarding Erg channel expression and function in electrically excitable glucagon and insulin producing cells of the pancreas is limited. In the present study Erg1 mRNA and protein were shown to be highly expressed in human and mouse islets and in alpha-TC6 and Min6 cells alpha- and beta-cell lines, respectively. Whole cell patch clamp recordings demonstrated the functional expression of Erg1 in alpha- and beta-cells, with rBeKm1, an Erg1 antagonist, blocking inward tail currents elicited by a double pulse protocol. Additionally, a small interference RNA approach targeting the kcnh2 gene (Erg1) induced a significant decrease of Erg1 inward tail current in Min6 cells. To investigate further the role of Erg channels in mouse and human islets, ratiometric Fura-2 AM Ca(2+)-imaging experiments were performed on isolated alpha- and beta-cells. Blocking Erg channels with rBeKm1 induced a transient cytoplasmic Ca(2+) increase in both alpha- and beta-cells. This resulted in an increased glucose-dependent insulin secretion, but conversely impaired glucagon secretion under low glucose conditions. Together, these data present Erg1 channels as new mediators of alpha- and beta-cell repolarization. However, antagonism of Erg1 has divergent effects in these cells; to augment glucose-dependent insulin secretion and inhibit low glucose stimulated glucagon secretion.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Alexandre B
authors.initials: AB
authors.lastname: Hardy
authors.forename: Jocelyn E Manning
authors.initials: JE
authors.lastname: Fox
authors.forename: Pejman Raeisi
authors.initials: PR
authors.lastname: Giglou
authors.forename: Nadeeja
authors.initials: N
authors.lastname: Wijesekara
authors.forename: Alpana
authors.initials: A
authors.lastname: Bhattacharjee
authors.forename: Sobia
authors.initials: S
authors.lastname: Sultan
authors.forename: Armen V
authors.initials: AV
authors.lastname: Gyulkhandanyan
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Gaisano
authors.forename: Patrick E
authors.initials: PE
authors.lastname: MacDonald
authors.forename: Michael B
authors.initials: MB
authors.lastname: Wheeler
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism; D050416:Glucagon-Secreting Cells / Q000737:chemistry*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000737:chemistry*; D007515:Islets of Langerhans / Q000166:cytology*; D008564:Membrane Potentials; D051379:Mice; D018408:Patch-Clamp Techniques
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D007328:Insulin; D005934:Glucagon; D002118:Calcium
references.citation: J Physiol. 1992 Sep;455:173-86
references.pmid: 1484353
references.citation: Philos Trans R Soc Lond B Biol Sci. 2005 Dec 29;360(1464):2211-25
references.pmid: 16321791
references.citation: Diabetes. 1967 Jan;16(1):35-9
references.pmid: 5333500
references.citation: Circulation. 2002 Feb 19;105(7):794-9
references.pmid: 11854117
references.citation: J Biol Chem. 2001 Mar 30;276(13):9868-76
references.pmid: 11136720
references.citation: J Physiol. 2000 Nov 1;528(Pt 3):509-20
references.pmid: 11060128
references.citation: Endocrinology. 2005 Nov;146(11):4766-75
references.pmid: 16109783
references.citation: Diabetes. 2008 Jun;57(6):1618-28
references.pmid: 18390794
references.citation: J Cell Mol Med. 2004 Jan-Mar;8(1):22-30
references.pmid: 15090257
references.citation: FEBS Lett. 1996 Apr 22;384(3):277-80
references.pmid: 8617371
references.citation: Pharmacol Rev. 2005 Dec;57(4):473-508
references.pmid: 16382104
references.citation: Digestion. 1997;58 Suppl 2:81-5
references.pmid: 9302496
references.citation: Transplantation. 2005 Sep 27;80(6):801-6
references.pmid: 16210968
references.citation: J Bioenerg Biomembr. 2003 Dec;35(6):687-96
references.pmid: 15000528
references.citation: Mol Endocrinol. 2001 Aug;15(8):1423-35
references.pmid: 11463864
references.citation: Am J Physiol Cell Physiol. 2007 Jan;292(1):C468-76
references.pmid: 16870833
references.citation: Mol Pharmacol. 2006 May;69(5):1673-83
references.pmid: 16497878
references.citation: J Neurosci. 2002 May 1;22(9):3414-25
references.pmid: 11978818
references.citation: Diabetes. 2004 Dec;53 Suppl 3:S181-9
references.pmid: 15561909
references.citation: Diabete Metab. 1994 Mar-Apr;20(2):138-45
references.pmid: 7528694
references.citation: Cell Mol Life Sci. 2007 Mar;64(6):768-80
references.pmid: 17322986
references.citation: J Physiol. 2001 Apr 1;532(Pt 1):143-63
references.pmid: 11283231
references.citation: Cardiovasc Res. 2005 Jan 1;65(1):128-37
references.pmid: 15621040
references.citation: Endocrinology. 1996 Feb;137(2):693-7
references.pmid: 8593819
references.citation: Pflugers Arch. 2003 Feb;445(5):589-600
references.pmid: 12634931
references.citation: FASEB J. 2000 Dec;14(15):2601-10
references.pmid: 11099479
references.citation: Cell. 2001 Jun 15;105(6):745-55
references.pmid: 11440717
references.citation: Am J Physiol Endocrinol Metab. 2003 Jan;284(1):E177-83
references.pmid: 12388130
references.citation: FASEB J. 1999 May;13(8):953-62
references.pmid: 10224238
references.citation: J Physiol. 2000 Nov 1;528(Pt 3):497-507
references.pmid: 11060127
references.citation: Endocrine. 2000 Dec;13(3):251-62
references.pmid: 11216635
references.citation: Trends Endocrinol Metab. 2008 Oct;19(8):277-84
references.pmid: 18771934
references.citation: Biochim Biophys Acta. 1979 Nov 1;587(4):579-92
references.pmid: 389293
references.citation: Pflugers Arch. 1999 Sep;438(4):428-36
references.pmid: 10519134
references.citation: Cell Metab. 2007 Sep;6(3):229-35
references.pmid: 17767909
references.citation: J Biol Chem. 2008 Apr 11;283(15):10184-97
references.pmid: 18250168
references.citation: Biophys J. 1996 Jun;70(6):2704-15
references.pmid: 8744308
references.citation: Diabetes. 2009 Feb;58(2):412-21
references.pmid: 19008345
references.citation: Diabetes. 2000 Sep;49(9):1500-10
references.pmid: 10969834
references.citation: PLoS Biol. 2007 Jun;5(6):e143
references.pmid: 17503968
references.citation: Br J Pharmacol. 1998 Feb;123(3):443-8
references.pmid: 9504385
references.citation: J Cardiovasc Pharmacol. 1991 Mar;17(3):480-7
references.pmid: 1711611
references.citation: Diabetes Care. 1990 Mar;13(3):340-63
references.pmid: 1689632
references.citation: J Neurosci. 1997 Dec 15;17(24):9423-32
references.pmid: 9390998
references.citation: J Physiol. 1997 Dec 15;505 ( Pt 3):677-88
references.pmid: 9457645
references.citation: Am J Physiol. 1990 Dec;259(6 Pt 2):H1881-9
references.pmid: 2260712
references.citation: J Biol Chem. 2002 Nov 22;277(47):44938-45
references.pmid: 12270920
references.citation: Diabetologia. 2003 Aug;46(8):1046-62
references.pmid: 12830383
references.citation: J Physiol. 2008 Oct 15;586(20):4877-90
references.pmid: 18718985
references.citation: J Physiol. 1999 Jan 15;514 ( Pt 2):579-91
references.pmid: 9852337
references.citation: Cell. 1995 Apr 21;81(2):299-307
references.pmid: 7736582