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Research ArticleArticle

Coassembly of Different Sulfonylurea Receptor Subtypes Extends the Phenotypic Diversity of ATP-sensitive Potassium (KATP) Channels

Adam Wheeler, Chuan Wang, Ke Yang, Kun Fang, Kevin Davis, Amanda M. Styer, Uyenlinh Mirshahi, Christophe Moreau, Jean Revilloud, Michel Vivaudou, Shunhe Liu, Tooraj Mirshahi and Kim W. Chan
Molecular Pharmacology November 2008, 74 (5) 1333-1344; DOI: https://doi.org/10.1124/mol.108.048355
Adam Wheeler
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Chuan Wang
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Ke Yang
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Kun Fang
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Kevin Davis
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Amanda M. Styer
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Uyenlinh Mirshahi
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Christophe Moreau
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Jean Revilloud
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Michel Vivaudou
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Shunhe Liu
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Tooraj Mirshahi
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Kim W. Chan
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Abstract

KATP channels are metabolic sensors and targets of potassium channel openers (KCO; e.g., diazoxide and pinacidil). They comprise four sulfonylurea receptors (SUR) and four potassium channel subunits (Kir6) and are critical in regulating insulin secretion. Different SUR subtypes (SUR1, SUR2A, SUR2B) largely determine the metabolic sensitivities and the pharmacological profiles of KATP channels. SUR1- but not SUR2-containing channels are highly sensitive to metabolic inhibition and diazoxide, whereas SUR2 channels are sensitive to pinacidil. It is generally believed that SUR1 and SUR2 are incompatible in channel coassembly. We used triple tandems, T1 and T2, each containing one SUR (SUR1 or SUR2A) and two Kir6.2Δ26 (last 26 residues are deleted) to examine the coassembly of different SUR. When T1 or T2 was expressed in Xenopus laevis oocytes, small whole-cell currents were activated by metabolic inhibition (induced by azide) plus a KCO (diazoxide for T1, pinacidil for T2). When coexpressed with any SUR subtype, the activated-currents were increased by 2- to 13-fold, indicating that different SUR can coassemble. Consistent with this, heteromeric SUR1+SUR2A channels were sensitive to azide, diazoxide, and pinacidil, and their single-channel burst duration was 2-fold longer than that of the T1 channels. Furthermore, SUR2A was coprecipitated with SUR1. Using whole-cell recording and immunostaining, heteromeric channels could also be detected when T1 and SUR2A were coexpressed in mammalian cells. Finally, the response of the SUR1+SUR2A channels to azide was found to be intermediate to those of the homomeric channels. Therefore, different SUR subtypes can coassemble into KATP channels with distinct metabolic sensitivities and pharmacological profiles.

Footnotes

  • This work was supported by National Institutes of Health grant DK60104 (to K.W.C.). T.M. is supported by beginning grant-in-aid 0765275U from the American Heart Association.

  • ABBREVIATIONS: SUR, sulfonylurea receptor; ABC, ATP-binding cassette; HA, hemagglutinin; TEVC, two-electrode voltage clamp; HK, high potassium; GFP, green fluorescent protein; CFP, cyan fluorescent protein; potassium channel opener; HEK, human embryonic kidney; diazoxide, 7-chloro-3-methyl-4H-1,2,4-benzothiadiazine 1,1-dioxide; ER, endoplasmic reticulum; glibenclamide, 5-chloro-N-[2-[4-(cyclohexylcarbamoylsulfamoyl)phenyl]ethyl]-2-methoxy-benzamide; pinacidil, 3-cyano-1-(4-pyridyl)-2-(1,2,2-trimethylpropyl)guanidine; Po, open probability.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • ↵1 Current affiliation: Department of Pediatrics, Case Western Reserve University, School of Medicine Rainbow Babies and Children's Hospital, Cleveland, Ohio.

  • ↵2 Current affiliation: Departments of Physiology and Medicine and the Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, Los Angeles, California.

  • ↵3 Current affiliation: Department of Pharmacological Sciences, CV Therapeutics, Palo Alto, California.

    • Received May 1, 2008.
    • Accepted August 21, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (5)
Molecular Pharmacology
Vol. 74, Issue 5
1 Nov 2008
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Research ArticleArticle

Coassembly of Different Sulfonylurea Receptor Subtypes Extends the Phenotypic Diversity of ATP-sensitive Potassium (KATP) Channels

Adam Wheeler, Chuan Wang, Ke Yang, Kun Fang, Kevin Davis, Amanda M. Styer, Uyenlinh Mirshahi, Christophe Moreau, Jean Revilloud, Michel Vivaudou, Shunhe Liu, Tooraj Mirshahi and Kim W. Chan
Molecular Pharmacology November 1, 2008, 74 (5) 1333-1344; DOI: https://doi.org/10.1124/mol.108.048355

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Research ArticleArticle

Coassembly of Different Sulfonylurea Receptor Subtypes Extends the Phenotypic Diversity of ATP-sensitive Potassium (KATP) Channels

Adam Wheeler, Chuan Wang, Ke Yang, Kun Fang, Kevin Davis, Amanda M. Styer, Uyenlinh Mirshahi, Christophe Moreau, Jean Revilloud, Michel Vivaudou, Shunhe Liu, Tooraj Mirshahi and Kim W. Chan
Molecular Pharmacology November 1, 2008, 74 (5) 1333-1344; DOI: https://doi.org/10.1124/mol.108.048355
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