Molecular determinants of ATP-sensitive potassium channel MgATPase activity: diabetes risk variants and diazoxide sensitivity

Molecular interactions between two residues in the sulfonylurea receptor (SUR) subunit of the ATP-sensitive potassium channel influence MgATPase activity. This interaction may provide a mechanism for the increased diabetes risk associated with a common channel variant and determines sensitivity to diazoxide.

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Abstract 1515: Regional Effects of Katp Channel Openers Reflect Distinct Atrial and Ventricular Katp Channel Structure in the Murine Heart

Circulation ◽

10.1161/circ.118.suppl_18.s_341-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Alexey V Glukhov ◽

Thomas P Flagg ◽

Vadim V Fedorov ◽

Igor R Efimov ◽

Colin G Nichols

Keyword(s):

Left Ventricle ◽

Right Ventricle ◽

Potassium Channel ◽

Katp Channel ◽

Channel Structure ◽

Receptor Type ◽

Optical Data ◽

Sulfonylurea Receptor ◽

Spatiotemporal Resolution ◽

Intact Mouse

Classically, cardiac sarcolemmal KATP channels are thought to be composed of Kir6.2 (inward-rectifier potassium channel 6.2, KCNJ11) and SUR2A (sulfonylurea receptor type 2A, ABCC9) subunits. However, the evidence is strong that SUR1 (sulfonylurea receptor type 1, ABCC8) subunits are also expressed in the heart and that they play a significant functional role in the atria. To examine this further, we have estimated the effects of potassium channel-opening drugs diazoxide (specific to SUR1 > SUR2A) and pinacidil (SUR2A > SUR1) in intact hearts from wild type (WT, n=6) and SUR1−/− mice (KO, n=3) that lack SUR1 subunits. Action potential duration (APD) in both atria and ventricles were estimated by optical mapping of posterior surface of Langendorff-perfused hearts using the voltage sensitive dye RH237 and high spatiotemporal resolution CMOS camera (100x100 pixels; 3,000 frames/sec). In WT hearts, diazoxide (300 μM) decreased APD in atria (from 33.6±2.1 ms to 25.5±1.0 ms, p<0.001) and did not change it in ventricles (60.0±8.5 ms vs 61.2±8.3 ms, NS). The absence of SUR1 in KO mice resulted in loss of efficacy of diazoxide in atria (37.5±0.7 ms vs 36.5±0.7 ms, NS). In contrast, pinacidil (300 μM) significantly decreased ventricular APD in both type of mice (from 60.0±8.5 ms to 30.5±4.2 ms in WT, p<0.001; and from 62.0±1.4 ms to 30.5±6.4 ms in KO, p<0.001) and did not change atrial APD in either WT or KO hearts. Glass microelectrode recordings from isolated superfused atria confirmed the optical data. In both WT and KO hearts, the APD in left ventricle was significantly longer and the effect of pinacidil was significantly greater than in right ventricle (APD decreasing by 56.3±4.2% and 62.3±12.0% in left ventricle vs 49.4±3.4% and 50.9±4.1% in right ventricle for WT and KO mice respectively, p<0.05). Similar differences between APDs in right and left atria were not observed. Collectively, these results indicate that in the intact mouse heart, significant differential KATP pharmacology in atria and ventricles results from SUR1 predominance in forming the atrial channel, highlighting an unappreciated heterogeneity of KATP function in the heart.

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Abstract 4735: Examining known diabetes risk variants for association with prostate cancer in a multiethnic population

10.1158/1538-7445.am10-4735 ◽

2010 ◽

Author(s):

Kevin M. Waters ◽

Daniel O. Stram ◽

Iona Cheng ◽

Frederick R. Schumacher ◽

Lynne R. Wilkens ◽

...

Keyword(s):

Prostate Cancer ◽

Diabetes Risk ◽

Risk Variants ◽

Multiethnic Population

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KCNJ11: Genetic Polymorphisms and Risk of Diabetes Mellitus

Journal of Diabetes Research ◽

10.1155/2015/908152 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 20

Author(s):

Polin Haghvirdizadeh ◽

Zahurin Mohamed ◽

Nor Azizan Abdullah ◽

Pantea Haghvirdizadeh ◽

Monir Sadat Haerian ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Secretion ◽

Katp Channel ◽

Pancreatic Beta Cells ◽

Current Evidence ◽

Nucleotide Polymorphisms ◽

Sulfonylurea Receptor ◽

Risk Variants ◽

Kcnj11 Gene ◽

Dm Type 2

Diabetes mellitus (DM) is a major worldwide health problem and its prevalence has been rapidly increasing in the last century. It is caused by defects in insulin secretion or insulin action or both, leading to hyperglycemia. Of the various types of DM, type 2 occurs most frequently. Multiple genes and their interactions are involved in the insulin secretion pathway. Insulin secretion is mediated through the ATP-sensitive potassium (KATP) channel in pancreatic beta cells. This channel is a heteromeric protein, composed of four inward-rectifier potassium ion channel (Kir6.2) tetramers, which form the pore of the KATP channel, as well as sulfonylurea receptor 1 subunits surrounding the pore. Kir6.2 is encoded by the potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) gene, a member of the potassium channel genes. Numerous studies have reported the involvement of single nucleotide polymorphisms of the KCNJ11 gene and their interactions in the susceptibility to DM. This review discusses the current evidence for the contribution of common KCNJ11 genetic variants to the development of DM. Future studies should concentrate on understanding the exact role played by these risk variants in the development of DM.

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