title: Calcium-activated and voltage-gated potassium channels of the pancreatic islet impart distinct and complementary roles during secretagogue induced electrical responses.
abstract: Glucose-induced β-cell action potential (AP) repolarization is regulated by potassium efflux through voltage gated (Kv) and calcium activated (K(Ca)) potassium channels. Thus, ablation of the primary Kv channel of the β-cell, Kv2.1, causes increased AP duration. However, Kv2.1(-/-) islet electrical activity still remains sensitive to the potassium channel inhibitor tetraethylammonium. Therefore, we utilized Kv2.1(-/-) islets to characterize Kv and K(Ca) channels and their respective roles in modulating the β-cell AP. The remaining Kv current present in Kv2.1(-/-) β-cells is inhibited with 5 μM CP 339818. Inhibition of the remaining Kv current in Kv2.1(-/-) mouse β-cells increased AP firing frequency by 39.6% but did not significantly enhance glucose stimulated insulin secretion (GSIS). The modest regulation of islet AP frequency by CP 339818 implicates other K(+) channels, possibly K(Ca) channels, in regulating AP repolarization. Blockade of the K(Ca) channel BK with slotoxin increased β-cell AP amplitude by 28.2%, whereas activation of BK channels with isopimaric acid decreased β-cell AP amplitude by 30.6%. Interestingly, the K(Ca) channel SK significantly contributes to Kv2.1(-/-) mouse islet AP repolarization. Inhibition of SK channels decreased AP firing frequency by 66% and increased AP duration by 67% only when Kv2.1 is ablated or inhibited and enhanced GSIS by 2.7-fold. Human islets also express SK3 channels and their β-cell AP frequency is significantly accelerated by 4.8-fold with apamin. These results uncover important repolarizing roles for both Kv and K(Ca) channels and identify distinct roles for SK channel activity in regulating calcium- versus sodium-dependent AP firing.
authors.affiliation: Deparment of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232-0615, USA. david.a.jacobson@vanderbilt.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Jacobson
authors.forename: Felipe
authors.initials: F
authors.lastname: Mendez
authors.forename: Michael
authors.initials: M
authors.lastname: Thompson
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Torres
authors.forename: Olivia
authors.initials: O
authors.lastname: Cochet
authors.forename: Louis H
authors.initials: LH
authors.lastname: Philipson
mesh_terms: D000634:Aminoquinolines; D000818:Animals; D002118:Calcium; D055724:Electrophysiological Phenomena / Q000187:drug effects* / Q000502:physiology; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007097:Imines; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D011804:Quinolines / Q000494:pharmacology; D014044:Tolbutamide / Q000494:pharmacology
chemical_list: D000634:Aminoquinolines; C529069:CP-339,818; D007004:Hypoglycemic Agents; D007097:Imines; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D011804:Quinolines; D014044:Tolbutamide; D005947:Glucose; D002118:Calcium