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Pharmacological properties and functional role of Kslow current in mouse pancreatic beta-cells: SK channels contribute to Kslow tail current and modulate insulin secretion.

Zhang M, Houamed K, Kupershmidt S, Roden D, Satin LS - J. Gen. Physiol. (2005)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23264, USA.

ABSTRACT
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 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.

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(A) UCL 1684 enhanced glucose-dependent insulin secretion from mouse islets. Islets were treated with different concentrations of UCL 1684 for 1 h using either basal (2.8 mM) or high (11.1 mM) glucose. Data shown were collected from four mice. ***, P < 0.001 vs. 2.8 mM glucose group. ##, P < 0.01; ###, P < 0.001 vs. untreated 11.1 mM glucose group. (B) AZ also increased insulin release from islets in 11.1 mM glucose. Data shown were obtained using islets isolated from four different mice. ***, P < 0.001 vs. 2.8 mM glucose group. ##, P < 0.01; ###, P < 0.001 vs. untreated 11.1 mM glucose group.
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fig7: (A) UCL 1684 enhanced glucose-dependent insulin secretion from mouse islets. Islets were treated with different concentrations of UCL 1684 for 1 h using either basal (2.8 mM) or high (11.1 mM) glucose. Data shown were collected from four mice. ***, P < 0.001 vs. 2.8 mM glucose group. ##, P < 0.01; ###, P < 0.001 vs. untreated 11.1 mM glucose group. (B) AZ also increased insulin release from islets in 11.1 mM glucose. Data shown were obtained using islets isolated from four different mice. ***, P < 0.001 vs. 2.8 mM glucose group. ##, P < 0.01; ###, P < 0.001 vs. untreated 11.1 mM glucose group.

Mentions: The increase in [Ca2+]i we observed following Kslow blockade suggested that glucose-dependent insulin secretion might also be increased by UCL 1684 or AZ. While 10 and 100 nM UCL 1684 had no effect on basal insulin secretion (measured in 2.8 mM glucose (P > 0.05), these concentrations increased glucose-stimulated insulin secretion from 722.3 ± 42.7 to 919.4 ± 54.2 or 1096.0 ± 54.2 pg · l−1 · islet−1 · h−1, respectively (Fig. 7 A, P < 0.01, n = 8).


Pharmacological properties and functional role of Kslow current in mouse pancreatic beta-cells: SK channels contribute to Kslow tail current and modulate insulin secretion.

Zhang M, Houamed K, Kupershmidt S, Roden D, Satin LS - J. Gen. Physiol. (2005)

(A) UCL 1684 enhanced glucose-dependent insulin secretion from mouse islets. Islets were treated with different concentrations of UCL 1684 for 1 h using either basal (2.8 mM) or high (11.1 mM) glucose. Data shown were collected from four mice. ***, P < 0.001 vs. 2.8 mM glucose group. ##, P < 0.01; ###, P < 0.001 vs. untreated 11.1 mM glucose group. (B) AZ also increased insulin release from islets in 11.1 mM glucose. Data shown were obtained using islets isolated from four different mice. ***, P < 0.001 vs. 2.8 mM glucose group. ##, P < 0.01; ###, P < 0.001 vs. untreated 11.1 mM glucose group.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2266621&req=5

fig7: (A) UCL 1684 enhanced glucose-dependent insulin secretion from mouse islets. Islets were treated with different concentrations of UCL 1684 for 1 h using either basal (2.8 mM) or high (11.1 mM) glucose. Data shown were collected from four mice. ***, P < 0.001 vs. 2.8 mM glucose group. ##, P < 0.01; ###, P < 0.001 vs. untreated 11.1 mM glucose group. (B) AZ also increased insulin release from islets in 11.1 mM glucose. Data shown were obtained using islets isolated from four different mice. ***, P < 0.001 vs. 2.8 mM glucose group. ##, P < 0.01; ###, P < 0.001 vs. untreated 11.1 mM glucose group.
Mentions: The increase in [Ca2+]i we observed following Kslow blockade suggested that glucose-dependent insulin secretion might also be increased by UCL 1684 or AZ. While 10 and 100 nM UCL 1684 had no effect on basal insulin secretion (measured in 2.8 mM glucose (P > 0.05), these concentrations increased glucose-stimulated insulin secretion from 722.3 ± 42.7 to 919.4 ± 54.2 or 1096.0 ± 54.2 pg · l−1 · islet−1 · h−1, respectively (Fig. 7 A, P < 0.01, n = 8).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University Medical Center, Richmond, VA 23264, USA.

ABSTRACT
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 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.

Show MeSH