Opposing effects of tenidap on the volume-regulated anion channel and KATP channel activity in rat pancreatic β-cells

The effect of metabolic inhibition on the blocking of β-cell ATP-sensitive K+ channels (KATP channels) by glibenclamide was investigated using a patch-clamp technique. Inhibition of KATP channels by glibenclamide was attenuated in the cell-attached mode under metabolic inhibition induced by 2,4-dinitrophenol. Under a low concentration (0.1 μM) of ATP applied in the inside-out mode, KATP channel activity was not fully abolished, even when a high dose of glibenclamide was applied, in contrast to the dose-dependent and complete KATP channel inhibition under 10 μM ATP. On the other hand, cibenzoline, a class Ia antiarrhythmic agent, inhibits KATP channel activity in a dose-dependent manner and completely blocks it, even under metabolic inhibition. In sulfonylurea receptor (SUR1)- and inward rectifier K+ channel (Kir6.2)-expressed proteins, cibenzoline binds directly to Kir6.2, unlike glibenclamide. Thus, KATPchannel inhibition by glibenclamide is impaired under the condition of decreased intracellular ATP in pancreatic β-cells, probably because of a defect in signal transmission between SUR1 and Kir6.2 downstream of the site of sulfonylurea binding to SUR1.

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Pharmacological modulation of KATP channels

Biochemical Society Transactions ◽

10.1042/bst0300333 ◽

2002 ◽

Vol 30 (2) ◽

pp. 333-339 ◽

Cited By ~ 43

Author(s):

F. M. Gribble ◽

F. Reimann

Keyword(s):

Type 2 Diabetes ◽

Cardiac Muscle ◽

Katp Channel ◽

Katp Channels ◽

Β Cells ◽

Pancreatic Β Cells ◽

Tissue Specific ◽

Pharmacological Modulation ◽

Clinical Conditions

Pharmacological modulation of ATP-sensitive K+ (KATP) channels is used in the treatment of a number of clinical conditions, including type 2 diabetes and angina. The sulphonylureas and related drugs, which are used to treat type 2 diabetes, stimulate insulin secretion by closing KATP channels in pancreatic β-cells. Agents used to treat angina, by contrast, act by opening KATP channels in vascular smooth and cardiac muscle. Both the therapeutic KATP channel inhibitors and the KATP channel openers target the sulphonylurea receptor (SUR) subunit of the KATP channel, which exists in several isoforms expressed in different tissues (SUR1 in pancreatic β-cells, SUR2A in cardiac muscle and SUR2B in vascular smooth muscle). The tissue-specific action of drugs that target the KATP channel is attributed to the properties of these different SUR subtypes. In this review, we discuss the molecular basis of tissue-specific drug action, and its implications for clinical practice.

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Diabetes induced by gain-of-function mutations in the Kir6.1 subunit of the KATP channel

The Journal of General Physiology ◽

10.1085/jgp.201611653 ◽

2016 ◽

Vol 149 (1) ◽

pp. 75-84 ◽

Cited By ~ 4

Author(s):

Maria S. Remedi ◽

Jonathan B. Friedman ◽

Colin G. Nichols

Keyword(s):

Insulin Secretion ◽

Katp Channel ◽

Vascular System ◽

Wild Type Mouse ◽

Neonatal Diabetes ◽

Katp Channels ◽

Β Cells ◽

Pancreatic Β Cells ◽

Gain Of Function ◽

Insulin Promoter

Gain-of-function (GOF) mutations in the pore-forming (Kir6.2) and regulatory (SUR1) subunits of KATP channels have been identified as the most common cause of human neonatal diabetes mellitus. The critical effect of these mutations is confirmed in mice expressing Kir6.2-GOF mutations in pancreatic β cells. A second KATP channel pore-forming subunit, Kir6.1, was originally cloned from the pancreas. Although the prominence of this subunit in the vascular system is well documented, a potential role in pancreatic β cells has not been considered. Here, we show that mice expressing Kir6.1-GOF mutations (Kir6.1[G343D] or Kir6.1[G343D,Q53R]) in pancreatic β cells (under rat-insulin-promoter [Rip] control) develop glucose intolerance and diabetes caused by reduced insulin secretion. We also generated transgenic mice in which a bacterial artificial chromosome (BAC) containing Kir6.1[G343D] is incorporated such that the transgene is only expressed in tissues where Kir6.1 is normally present. Strikingly, BAC-Kir6.1[G343D] mice also show impaired glucose tolerance, as well as reduced glucose- and sulfonylurea-dependent insulin secretion. However, the response to K+ depolarization is intact in Kir6.1-GOF mice compared with control islets. The presence of native Kir6.1 transcripts was demonstrated in both human and wild-type mouse islets using quantitative real-time PCR. Together, these results implicate the incorporation of native Kir6.1 subunits into pancreatic KATP channels and a contributory role for these subunits in the control of insulin secretion.

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cAMP-independent decrease of ATP-sensitive K+ channel activity by GLP-1 in rat pancreatic β-cells

Pflügers Archiv - European Journal of Physiology ◽

10.1007/s004240000279 ◽

2000 ◽

Vol 440 (4) ◽

pp. 566-572 ◽

Cited By ~ 4

Author(s):

Sechiko Suga ◽

Takahiro Kanno ◽

Yoshiji Ogawa ◽

Teruko Takeo ◽

Noritaka Kamimura ◽

...

Keyword(s):

K Channel ◽

Channel Activity ◽

Β Cells ◽

Pancreatic Β Cells

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The Imidazoline RX871024 Stimulates Insulin Secretion in Pancreatic β-Cells from Mice Deficient in KATP Channel Function

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.2001.5068 ◽

2001 ◽

Vol 284 (4) ◽

pp. 918-922 ◽

Cited By ~ 14

Author(s):

Alexander M. Efanov ◽

Marianne Høy ◽

Robert Bränström ◽

Sergei V. Zaitsev ◽

Mark A. Magnuson ◽

...

Keyword(s):

Insulin Secretion ◽

Katp Channel ◽

Β Cells ◽

Pancreatic Β Cells ◽

Channel Function

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Stevioside acts directly on pancreatic β cells to secrete insulin: Actions independent of cyclic adenosine monophosphate and adenosine triphosphate—sensitivie K+-channel activity

Metabolism ◽

10.1016/s0026-0495(00)91325-8 ◽

2000 ◽

Vol 49 (2) ◽

pp. 208-214 ◽

Cited By ~ 147

Author(s):

P.B. Jeppesen ◽

S. Gregersen ◽

C.R. Poulsen ◽

K. Hermansen

Keyword(s):

Adenosine Triphosphate ◽

Cyclic Adenosine Monophosphate ◽

Adenosine Monophosphate ◽

K Channel ◽

Channel Activity ◽

Β Cells ◽

Pancreatic Β Cells

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Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating

eLife ◽

10.7554/elife.24149 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 96

Author(s):

Gregory M Martin ◽

Craig Yoshioka ◽

Emily A Rex ◽

Jonathan F Fay ◽

Qing Xie ◽

...

Keyword(s):

Symmetry Axis ◽

Transmembrane Domain ◽

Katp Channels ◽

Structural Basis ◽

Channel Activity ◽

Membrane Excitability ◽

Β Cells ◽

Pancreatic Β Cells ◽

Binding Domains ◽

Channel Assembly

KATP channels are metabolic sensors that couple cell energetics to membrane excitability. In pancreatic β-cells, channels formed by SUR1 and Kir6.2 regulate insulin secretion and are the targets of antidiabetic sulfonylureas. Here, we used cryo-EM to elucidate structural basis of channel assembly and gating. The structure, determined in the presence of ATP and the sulfonylurea glibenclamide, at ~6 Å resolution reveals a closed Kir6.2 tetrameric core with four peripheral SUR1s each anchored to a Kir6.2 by its N-terminal transmembrane domain (TMD0). Intricate interactions between TMD0, the loop following TMD0, and Kir6.2 near the proposed PIP2 binding site, and where ATP density is observed, suggest SUR1 may contribute to ATP and PIP2 binding to enhance Kir6.2 sensitivity to both. The SUR1-ABC core is found in an unusual inward-facing conformation whereby the two nucleotide binding domains are misaligned along a two-fold symmetry axis, revealing a possible mechanism by which glibenclamide inhibits channel activity.

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