Pharmacological properties and functional role of Kslow current in mouse pancreatic beta-cells: SK channels contribute to Kslow tail current and modulate insulin secretion.
The pharmacological properties of slow Ca(2+)-activated K(+) current (K(slow)) were investigated in mouse pancreatic beta-cells and islets to understand how K(slow) contributes to the control of islet bursting, [Ca(2+)](i) oscillations, and insulin secretion. K(slow) was insensitive to apamin or the K(ATP) channel inhibitor tolbutamide, but UCL 1684, a potent and selective nonpeptide SK channel blocker reduced the amplitude of K(slow) tail current in voltage-clamped mouse beta-cells. K(slow) was also selectively and reversibly inhibited by the class III antiarrythmic agent azimilide (AZ). In isolated beta-cells or islets, pharmacologic inhibition of K(slow) by UCL 1684 or AZ depolarized beta-cell silent phase potential, increased action potential firing, raised [Ca(2+)](i), and enhanced glucose-dependent insulin secretion. AZ inhibition of K(slow) also supported mediation by SK, rather than cardiac-like slow delayed rectifier channels since bath application of AZ to HEK 293 cells expressing SK3 cDNA reduced SK current. Further, AZ-sensitive K(slow) current was extant in beta-cells from KCNQ1 or KCNE1 null mice lacking cardiac slow delayed rectifier currents. These results strongly support a functional role for SK channel-mediated K(slow) current in beta-cells, and suggest that drugs that target SK channels may represent a new approach for increasing glucose-dependent insulin secretion. The apamin insensitivity of beta-cell SK current suggests that beta-cells express a unique SK splice variant or a novel heteromultimer consisting of different SK subunits.
Zhang
Min
M
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23264, USA.
Houamed
Khaled
K
Kupershmidt
Sabina
S
Roden
Dan
D
Satin
Leslie S
LS
D000473:Alkanes / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D006827:Hydantoins; D048289:Imidazolidines / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D010879:Piperazines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism; D011806:Quinolinium Compounds / Q000494:pharmacology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
C110349:6,10-diaza-3(1,3),8(1,4)dibenzena-1,5(1,4)diquinolinacyclodecaphane; D000473:Alkanes; D002121:Calcium Channel Blockers; D006827:Hydantoins; D048289:Imidazolidines; D007328:Insulin; D051657:KCNQ1 Potassium Channel; C092068:Kcne1 protein, mouse; C496900:Kcnn3 protein, mouse; D010879:Piperazines; D024642:Potassium Channels, Voltage-Gated; D011806:Quinolinium Compounds; D051640:Small-Conductance Calcium-Activated Potassium Channels; C086123:azimilide; D005947:Glucose; D011188:Potassium; D002118:Calcium