Abstract
In responding to cytoplasmic nucleotide levels, ATP-sensitive potassium (KATP) channel activity provides a unique link between cellular energetics and electrical excitability. Over the past ten years, a steady drumbeat of crystallographic and electrophysiological studies has led to detailed structural and kinetic models that define the molecular basis of channel activity. In parallel, the uncovering of disease-causing mutations of KATP has led to an explanation of the molecular basis of disease and, in turn, to a better understanding of the structural basis of channel function.
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References
Miki, T. & Seino, S. Roles of KATP channels as metabolic sensors in acute metabolic changes. J. Mol. Cell. Cardiol. 38, 917–925 (2005).
Bryan, J., Vila-Carriles, W. H., Zhao, G., Babenko, A. P. & Aguilar-Bryan, L. Toward linking structure with function in ATP-sensitive K+ channels. Diabetes 53 (Suppl. 3), S104–S112 (2004).
Ashcroft, F. M. ATP-sensitive potassium channelopathies: focus on insulin secretion. J. Clin. Invest. 115, 2047–2058 (2005).
Flagg, T. P. & Nichols, C. Sarcolemmal KATP channels: what do we really know? J. Mol. Cell. Cardiol. 39, 61–70 (2005).
Inagaki, N. et al. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science 270, 1166–1170 (1995).
Inagaki, N. et al. A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels. Neuron 16, 1011–1017 (1996).
Yamada, M. et al. Sulphonylurea receptor 2B and Kir6.1 form a sulphonylurea-sensitive but ATP-insensitive K+ channel. J. Physiol. (Lond.) 499, 715–720 (1997).
Shyng, S. & Nichols, C. G. Octameric stoichiometry of the KATP channel complex. J. Gen. Physiol. 110, 655–664 (1997).
Clement, J. P. IV et al. Association and stoichiometry of KATP channel subunits. Neuron 18, 827–838 (1997).
Neagoe, I. & Schwappach, B. Pas de deux in groups of four—the biogenesis of KATP channels. J. Mol. Cell. Cardiol. 38, 887–894 (2005).
Doyle, D. A. et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280, 69–77 (1998).
Nishida, M. & MacKinnon, R. Structural basis of inward rectification. Cytoplasmic pore of the G protein-gated inward rectifier GIRK1 at 1.8 Å resolution. Cell 111, 957–965 (2002).
Pegan, S. et al. Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification. Nature Neurosci. 8, 279–287 (2005).
Kuo, A. et al. Crystal structure of the potassium channel KirBac1.1 in the closed state. Science 300, 1922–1926 (2003).
Kuo, A., Domene, C., Johnson, L. N., Doyle, D. A. & Venien-Bryan, C. Two different conformational states of the KirBac3.1 potassium channel revealed by electron crystallography. Structure 13, 1463–1472 (2005).
Antcliff, J. F., Haider, S., Proks, P., Sansom, M. S. & Ashcroft, F. M. Functional analysis of a structural model of the ATP-binding site of the KATP channel Kir6.2 subunit. EMBO J. 24, 229–239 (2005).
Haider, S., Antcliff, J. F., Proks, P., Sansom, M. S. & Ashcroft, F. M. Focus on Kir6.2: a key component of the ATP-sensitive potassium channel. J. Mol. Cell. Cardiol. 38, 927–936 (2005).
Enkvetchakul, D. et al. Functional characterization of a prokaryotic Kir channel. J. Biol. Chem. 279, 47076–47080 (2004).
Enkvetchakul, D., Jeliazkova, I. & Nichols, C. G. Direct modulation of Kir channel gating by membrane phosphatidylinositol 4,5-bisphosphate. J. Biol. Chem. 280, 35785–35788 (2005).
Baukrowitz, T. et al. PIP2 and PIP as determinants for ATP inhibition of KATP channels. Science 282, 1141–1144 (1998).
Fan, Z. & Makielski, J. C. Anionic phospholipids activate ATP-sensitive potassium channels. J. Biol. Chem. 272, 5388–5395 (1997).
Shyng, S. L. & Nichols, C. G. Membrane phospholipid control of nucleotide sensitivity of KATP channels. Science 282, 1138–1141 (1998).
Chan, K. W., Zhang, H., Mishahi, T. & Logothetis, D. E. Characterization of the interaction between the N-terminal transmembrane domain of the sulfonylurea receptor (SUR1) and Kir6.2. Biophys. J. 82, 590a (2002).
Babenko, A. P. & Bryan, J. SUR-dependent modulation of KATP channels by an N-terminal KIR6.2 peptide. Defining intersubunit gating interactions. J. Biol. Chem. 277, 43997–44004 (2002).
Babenko, A. P. & Bryan, J. SUR domains that associate with and gate KATP pores define a novel gatekeeper. J. Biol. Chem. 278, 41577–41580 (2003).
Campbell, J. D., Proks, P., Lippiat, J. D., Sansom, M. S. & Ashcroft, F. M. Identification of a functionally important negatively charged residue within the second catalytic site of the SUR1 nucleotide-binding domains. Diabetes 53 (Suppl. 3), S123–S127 (2004).
Hung, L. W. et al. Crystal structure of the ATP-binding subunit of an ABC transporter. Nature 396, 703–707 (1998).
Hopfner, K. P. et al. Structural biology of Rad50 ATPase: ATP-driven conformational control in DNA double-strand break repair and the ABC-ATPase superfamily. Cell 101, 789–800 (2000).
Locher, K. P., Lee, A. T. & Rees, D. C. The E. coli BtuCD structure: a framework for ABC transporter architecture and mechanism. Science 296, 1091–1098 (2002).
Matsuo, M., Kioka, N., Amachi, T. & Ueda, K. ATP binding properties of the nucleotide-binding folds of SUR1. J. Biol. Chem. 274, 37479–37482 (1999).
Hough, E., Mair, L., Mackenzie, W. & Sivaprasadarao, A. Expression, purification, and evidence for the interaction of the two nucleotide-binding folds of the sulphonylurea receptor. Biochem. Biophys. Res. Commun. 294, 191–197 (2002).
Mikhailov, M. V. & Ashcroft, S. J. H. Interactions of the sulfonylurea receptor 1 subunit in the molecular assembly of β-cell K-ATP channels. J. Biol. Chem. 275, 3360–3364 (2000).
Mikhailov, M. V. et al. 3-D structural and functional characterization of the purified KATP channel complex Kir6.2–SUR1. EMBO J. 24, 4166–4175 (2005).
Proks, P., Capener, C. E., Jones, P. & Ashcroft, F. M. Mutations within the P-loop of Kir6.2 modulate the intraburst kinetics of the ATP-sensitive potassium channel. J. Gen. Physiol. 118, 341–353 (2001).
Jiang, Y. et al. The open pore conformation of potassium channels. Nature 417, 523–526 (2002).
Enkvetchakul, D. & Nichols, C. G. Gating mechanism of KATP channels: function fits form. J. Gen. Physiol. 122, 471–480 (2003).
Sackin, H., Nanazashvili, M., Palmer, L. G., Krambis, M. & Walters, D. E. Structural locus of the pH gate in the Kir1.1 inward rectifier channel. Biophys. J. 88, 2597–2606 (2005).
Drain, P., Geng, X. & Li, L. Concerted gating mechanism underlying KATP channel inhibition by ATP. Biophys. J. 86, 2101–2112 (2004).
Loussouarn, G., Phillips, L. R., Masia, R., Rose, T. & Nichols, C. G. Flexibility of the Kir6.2 inward rectifier K+ channel pore. Proc. Natl Acad. Sci. USA 98, 4227–4232 (2001).
Lu, T., Nguyen, B., Zhang, X. & Yang, J. Architecture of a K+ channel inner pore revealed by stoichiometric covalent modification. Neuron 22, 571–580 (1999).
Domene, C., Doyle, D. A. & Venien-Bryan, C. Modeling of an ion channel in its open conformation. Biophys. J. 89, L01–L03 (2005).
Phillips, L. R. & Nichols, C. G. Ligand-induced closure of inward rectifier Kir6.2 channels traps spermine in the pore. J. Gen. Physiol. 122, 795–804 (2003).
Phillips, L. R., Enkvetchakul, D. & Nichols, C. G. Gating dependence of inner pore access in inward rectifier K+ channels. Neuron 37, 953–962 (2003).
Enkvetchakul, D., Loussouarn, G., Makhina, E., Shyng, S. L. & Nichols, C. G. The kinetic and physical basis of KATP channel gating: toward a unified molecular understanding. Biophys. J. 78, 2334–2348 (2000).
Markworth, E., Schwanstecher, C. & Schwanstecher, M. ATP4− mediates closure of pancreatic β-cell ATP-sensitive potassium channels by interaction with 1 of 4 identical sites. Diabetes 49, 1413–1418 (2000).
Proks, P., Gribble, F. M., Adhikari, R., Tucker, S. J. & Ashcroft, F. M. Involvement of the N-terminus of Kir6.2 in the inhibition of the KATP channel by ATP. J. Physiol. (Lond.) 514, 19–25 (1999).
Li, L., Wang, J. & Drain, P. The I182 region of Kir6.2 is closely associated with ligand binding in KATP channel inhibition by ATP. Biophys. J. 79, 841–852 (2000).
Tucker, S. J., Gribble, F. M., Zhao, C., Trapp, S. & Ashcroft, F. M. Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor. Nature 387, 179–183 (1997).
Shyng, S. L., Cukras, C. A., Harwood, J. & Nichols, C. G. Structural determinants of PIP2 regulation of inward rectifier KATP channels. J. Gen. Physiol. 116, 599–608 (2000).
Drain, P., Li, L. & Wang, J. KATP channel inhibition by ATP requires distinct functional domains of the cytoplasmic C terminus of the pore-forming subunit. Proc. Natl Acad. Sci. USA 95, 13953–13958 (1998).
MacGregor, G. G. et al. Nucleotides and phospholipids compete for binding to the C terminus of KATP channels. Proc. Natl Acad. Sci. USA 99, 2726–2731 (2002).
Nichols, C. G. et al. Adenosine diphosphate as an intracellular regulator of insulin secretion. Science 272, 1785–1787 (1996).
Lammens, A., Schele, A. & Hopfner, K. P. Structural biochemistry of ATP-driven dimerization and DNA-stimulated activation of SMC ATPases. Curr. Biol. 14, 1778–1782 (2004).
Smith, P. C. et al. ATP binding to the motor domain from an ABC transporter drives formation of a nucleotide sandwich dimer. Mol. Cell 10, 139–149 (2002).
Matsuo, M., Tanabe, K., Kioka, N., Amachi, T. & Ueda, K. Different binding properties and affinities for ATP and ADP among sulfonylurea receptor subtypes, SUR1, SUR2A, and SUR2B. J. Biol. Chem. 275, 28757–28763 (2000).
Ueda, K., Komine, J., Matsuo, M., Seino, S. & Amachi, T. Cooperative binding of ATP and MgADP in the sulfonylurea receptor is modulated by glibenclamide. Proc. Natl Acad. Sci. USA 96, 1268–1272 (1999).
Zingman, L. V. et al. Signaling in channel/enzyme multimers: ATPase transitions in SUR module gate ATP-sensitive K+ conductance. Neuron 31, 233–245 (2001).
Bienengraeber, M. et al. ATPase activity of the sulfonylurea receptor: a catalytic function for the KATP channel complex. FASEB J. 14, 1943–1952 (2000).
Masia, R., Enkvetchakul, D. & Nichols, C. Differential nucleotide regulation of KATP channels by SUR1 and SUR2A. J. Mol. Cell. Cardiol. 39, 491–501 (2005).
Shyng, S., Ferrigni, T. & Nichols, C. G. Regulation of KATP channel activity by diazoxide and MgADP. Distinct functions of the two nucleotide binding folds of the sulfonylurea receptor. J. Gen. Physiol. 110, 643–654 (1997).
Gribble, F. M., Tucker, S. J. & Ashcroft, F. M. The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide. EMBO J. 16, 1145–1152 (1997).
Zingman, L. V. et al. Tandem function of nucleotide binding domains confers competence to sulfonylurea receptor in gating ATP-sensitive K+ channels. J. Biol. Chem. 277, 14206–14210 (2002).
Seino, S. & Miki, T. Gene targeting approach to clarification of ion channel function: studies of Kir6.x null mice. J. Physiol. (Lond.) 554, 295–300 (2004).
Miki, T. et al. Defective insulin secretion and enhanced insulin action in KATP channel- deficient mice. Proc. Natl Acad. Sci. USA 95, 10402–10406 (1998).
Seghers, V., Nakazaki, M., DeMayo, F., Aguilar-Bryan, L. & Bryan, J. Sur1 knockout mice. A model for KATP channel-independent regulation of insulin secretion. J. Biol. Chem. 275, 9270–9277 (2000).
Shiota, C. et al. Sulfonylurea receptor type 1 knock-out mice have intact feeding-stimulated insulin secretion despite marked impairment in their response to glucose. J. Biol. Chem. 277, 37176–37183 (2002).
Chutkow, W. A. et al. Disruption of Sur2-containing KATP channels enhances insulin-stimulated glucose uptake in skeletal muscle. Proc. Natl Acad. Sci. USA 98, 11760–11764 (2001).
Suzuki, M. et al. Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice. Circ. Res. 88, 570–577 (2001).
Miki, T. et al. Mouse model of Prinzmetal angina by disruption of the inward rectifier Kir6.1. Nature Med. 8, 466–472 (2002).
Chutkow, W. A. et al. Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 KATP channels. J. Clin. Invest. 110, 203–208 (2002).
Koster, J. C., Permutt, A. & Nichols, C. G. Diabetes and insulin secretion: the ATP-sensitive K+ channel (KATP) connection. Diabetes 54, 3065–3072 (2005).
Hattersley, A. T. & Ashcroft, F. M. Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy. Diabetes 54, 2503–2513 (2005).
Sharma, N., Crane, A., Gonzalez, G., Bryan, J. & Aguilar-Bryan, L. Familial hyperinsulinism and pancreatic β-cell ATP-sensitive potassium channels. Kidney Int. 57, 803–808 (2000).
Nestorowicz, A. et al. Genetic heterogeneity in familial hyperinsulinism. Hum. Mol. Genet. 7, 1119–1128 (1998).
Tornovsky, S. et al. Hyperinsulinism of infancy: novel ABCC8 and KCNJ11 mutations and evidence for additional locus heterogeneity. J. Clin. Endocrinol. Metab. 89, 6224–6234 (2004).
Shyng, S. L. et al. Functional analyses of novel mutations in the sulfonylurea receptor 1 associated with persistent hyperinsulinemic hypoglycemia of infancy. Diabetes 47, 1145–1151 (1998).
Cartier, E., Conti, L. R., Vandenberg, C. A. & Shyng, S.-L. Defective trafficking and function of KATP channels caused by a sulfonylurea receptor 1 mutation associated with persistent hyperinsulinemic hypoglycemia of infancy. Proc. Natl Acad. Sci. USA 98, 2882–2887 (2001).
Partridge, C. J., Beech, D. J. & Sivaprasadarao, A. Identification and pharmacological correction of a membrane trafficking defect associated with a mutation in the sulfonylurea receptor causing familial hyperinsulinism. J. Biol. Chem. 276, 35947–35952 (2001).
Yan, F. et al. Sulfonylureas correct trafficking defects of ATP-sensitive potassium channels caused by mutations in the sulfonylurea receptor. J. Biol. Chem. 279, 11096–11105 (2004).
Gloyn, A. L. et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N. Engl. J. Med. 350, 1838–1849 (2004).
Proks, P. et al. Molecular basis of Kir6.2 mutations associated with neonatal diabetes plus neurological features. Proc. Natl Acad. Sci. USA 101, 17539–17544 (2004).
Koster, J. C., Remedi, M. S., Dao, C. & Nichols, C. G. ATP and sulfonylurea sensitivity of mutant ATP-sensitive K+ channels in neonatal diabetes: implications for pharmacogenomic therapy. Diabetes 54, 2645–2654 (2005).
Tucker, S. J. et al. Molecular determinants of KATP channel inhibition by ATP. EMBO J. 17, 3290–3296 (1998).
Schwanstecher, C., Meyer, U. & Schwanstecher, M. KIR6.2 polymorphism predisposes to type 2 diabetes by inducing overactivity of pancreatic β-cell ATP-sensitive K+ channels. Diabetes 51, 875–879 (2002).
Yorifuji, T. et al. The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 90, 3174–3178 (2005).
Massa, O. et al. KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum. Mutat. 25, 22–27 (2005).
Sagen, J. V. et al. Permanent neonatal diabetes due to mutations in KCNJ11 encoding Kir6.2: patient characteristics and initial response to sulfonylurea therapy. Diabetes 53, 2713–2718 (2004).
Zung, A., Glaser, B., Nimri, R. & Zadik, Z. Glibenclamide treatment in permanent neonatal diabetes mellitus due to an activating mutation in Kir6.2. J. Clin. Endocrinol. Metab. 89, 5504–5507 (2004).
Crawford, R. M. et al. M-LDH serves as a sarcolemmal KATP channel subunit essential for cell protection against ischemia. EMBO J. 21, 3936–3948 (2002).
Chowdhury, P. D. et al. The glycolytic enzymes, glyceraldehyde-3-phosphate dehydrogenase, triose-phosphate isomerase, and pyruvate kinase are components of the KATP channel macromolecular complex and regulate its function. J. Biol. Chem. 280, 38464–38470 (2005).
Cartier, E. A., Shen, S. & Shyng, S. L. Modulation of the trafficking efficiency and functional properties of ATP-sensitive potassium channels through a single amino acid in the sulfonylurea receptor. J. Biol. Chem. 278, 7081–7090 (2003).
Haider, S., Grottesi, A., Hall, B. A., Ashcroft, F. M. & Sansom, M. S. Conformational dynamics of the ligand-binding domain of inward rectifier K channels as revealed by molecular dynamics simulations: toward an understanding of Kir channel gating. Biophys. J. 88, 3310–3320 (2005).
Acknowledgements
I am grateful to R. Masia, B. Koster, D. Enkvetchakul, H. Kurata and T. Flagg for providing suggestions on the text, and to R. Masia, D. Enkvetchakul, F. Ashcroft and M. Sansom for providing molecular models of SUR1 NBFs and Kir6.2.
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Nichols, C. KATP channels as molecular sensors of cellular metabolism. Nature 440, 470–476 (2006). https://doi.org/10.1038/nature04711
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DOI: https://doi.org/10.1038/nature04711
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