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IUPHAR Compendium of Voltage-Gated Ion Channels 2005

International Union of Pharmacology. LIV. Nomenclature and Molecular Relationships of Inwardly Rectifying Potassium Channels

Division of Biophysics and Neurobiology, Department of Molecular Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki, Aichi, Japan (Y.K.); Vollum Institute, Oregon Health Sciences University, Portland, Oregon (J.P.A.); Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, Boston, Massachusetts (D.E.C.); Howard Hughes Medical Institute, Department of Physiology and Biochemistry, University of California, San Francisco, San Francisco, California (L.Y.J.); Institute of Physiology, University of Würzburg, Würzburg, Germany (A.K.); Department of Pharmacology II, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan (Y.K.); Institut de Pharmacologie Moleculaire et Cellulaire, Centre National de la Recherche Scientifique-Unité Propre de Recherche 411,Valbonne, France (M.L.); Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri (C.G.N.); Division of Cellular and Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Hyago, Japan (S.S.); and Department of Molecular, Cellular and Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, California (C.A.V.)

Introduction

Since the initial cDNA cloning of the first inward rectifiers K_ir1.1 (ROMK1) and K_ir2.1 (IRK1) in 1993, a succession of new members of this family have been identified, including the G protein-coupled K_ir3 and the ATP-sensitive K_ir6. These channels play an important physiological role in the function of many organs, including brain, heart, kidney, endocrine cells, ears, and retina. The phylogenic tree shown in Fig. 1 illustrates the relationships between the seven K_ir subfamilies based on amino acid sequence alignments. No new members of this family have been identified since this tree appeared in the 2002 edition of The IUPHAR Compendium of Voltage-Gated Ion Channels, and it is unlikely that any other members remain to be discovered.

View larger version (25K): [in this window] [in a new window]   FIG. 1. Phylogenetic tree of Kir channels. Amino acid sequence alignments and phylogenetic analysis for the 15 known members of the human Kir family were generated as described in the legend for Fig. 1 of "LIII. Nomenclature and Molecular Relationships of Voltage-Gated Potassiuim Channels". No new channels have been added to this topology since it appeared in the earlier edition of this compendium. International Union of Pharmacology and HUGO Gene Nomenclature Committee names of the genes are shown together with their chromosomal localization.

• The interaction of K_ir1.1 with Na⁺/H⁺ exchange regulatory factor 2 in the postsynaptic density 95/disc-large/zona occludens (PDZ) complex was reported (Yoo et al., 2004).
  
• The assembly of K_ir2.1 channels with synapse-associated protein 97 (SAP97), calmodulin-dependent serine protein kinase (CASK), Veli, and Mint1 and their contribution to protein trafficking was shown (Leonoudakis et al., 2004).
  
• K_ir4.1 in glial cells and K_ir2.2 in muscle were shown to associate with the dystrophin-glycoprotein complex via -syntrophin (Connors et al., 2004).
  
• K_ir4.1 has been associated with epilepsy in both causative and protective roles (Buono et al., 2004; Ferraro et al., 2004; Leonoudakis et al., 2004).
  
• It was shown that the loss of K_ir 4.1 expression abolishes endocochlear potential and causes deafness in Pendred syndrome (Wangemann et al., 2004).
  
• The disruption of K_ir6.1 gene in mice was reported to cause phenotypes similar to those of vasospastic (Prinzmetal) angina (Miki et al., 2002).
  
• It was shown that an activating mutation of K_ir6.2 causes permanent neonatal diabetes (Gloyn et al., 2004).
  

Although it is not discussed herein, among the most exciting recent developments are those involving X-ray crystal structure analysis, including studies describing the structure of the cytoplasmic region of K_ir3.1 (Nishida and MacKinnon, 2002), the entire structure of the bacterial K_ir1.1 channel (Kuo et al., 2003), and the cytoplasmic region of K_ir2.1 (Pegan et al., 2005). These studies demonstrated that inward rectifier K⁺ channels have a long cytoplasmic pore and confirmed the significance of negatively charged amino acids on the wall of the cytoplasmic pore that have been known to play critical roles for inward rectification. They also provided structure-based clues for the regulation mechanisms of gating by ligands such as G proteins and phosphatidylinositol 4,5-bisphosphate. The information yielded by analysis of crystal structures is extremely valuable since it will enable more precise approaches to establishing structure-function relationships. Also noteworthy are published studies on the dynamic aspects of channel function using fluorescence resonance energy transfer analysis of fluorescent-labeled molecules (Riven et al., 2003). Knowledge of these dynamic aspects of K_ir channel function may also be expected to expand in the near future.

A great deal of additional knowledge on K_ir function, structure-function relationships, regulation of expression, and links with diseases has been accumulated. Since it is not possible to describe it in detail here, we refer the reader instead to several excellent recent reviews (Stanfield et al., 2002; Bichet et al., 2003; Lu, 2004). See Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 for K_ir1 through K_ir7.1.

Acknowledgements

We gratefully acknowledge the support of Drs. Atsushi Inanobe (Kurachi Lab), Wade Pearson (Nichols Lab), and Florian Lesage (Lazdunski Lab) and the contributions of Dr. Henry Lester (California Institute of Technology, Pasadena, CA) to the earlier edition of this compendium.

Address correspondence to: Dr. Yoshihiro Kubo, Division of Biophysics and Neurobiology, Department of Molecular Physiology, National Institute for Physiological Sciences, Nishigoh-naka 38, Myodaiji, Okazaki, Aichi 444-8585, Japan.

Footnotes

The authors serve as the Subcommittee on K_ir channels of the Nomenclature Committee of the International Union of Pharmacology.

Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org.

doi:10.1124/pr.57.4.11.

References

Bichet D, Haass FA, and Jan LY (2003) Merging functional studies with structures of inward rectifier K⁺ channels. Nat Rev Neurosci 4: 957-967.[CrossRef][Medline]

Buono RJ, Lohoff FW, Sander T, Sperling MR, O'Connor MJ, Dlugos DJ, Ryan SG, den GT, Zhao H, Scattergood TM, et al. (2004) Association between variation in the human KCNJ10 potassium ion channel gene and seizure susceptibility. Epilepsy Res 58: 175-183.[Medline]

Connors NC, Adams ME, Froehner SC, and Kofuji P (2004) The potassium channel Kir4.1 associates with the dystrophin-glycoprotein complex via alpha-syntrophin in glia. J Biol Chem 279: 28387-28392.[Abstract/Free Full Text]

Ferraro TN, Golden GT, Smith GG, Martin JF, Lohoff FW, Gieringer TA, Zamboni D, Schwebel CL, Press DM, Kratzer SO, et al. (2004) Fine mapping of a seizure susceptibility locus on mouse chromosome 1: nomination of Kcnj10 as a causative gene. Mamm Genome 15: 239-251.[CrossRef][Medline]

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Kuo A, Gulbis JM, Antcliff JF, Rahman T, Lowe ED, Zimmer J, Cuthbertson J, Ashcroft FM, Ezaki T, and Doyle DA (2003) Crystal structure of the potassium channel KirBac1.1 in the closed state. Science (Wash DC) 300: 1922-1926.[Abstract/Free Full Text]

Leonoudakis D, Conti LR, Anderson S, Radeke CM, McGuire LMM, Adams ME, Froehner SC, Yates JR 3rd, and Vandenberg CA (2004) Protein trafficking and anchoring complexes revealed by proteomic analysis of inward rectifier potassium channel (Kir2x)-associated proteins. J Biol Chem 279: 22331-22346.[Abstract/Free Full Text]

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Pegan S, Arrabit C, Zhou W, Kwiatkowski W, Collins A, Slesinger PA, and Choe S (2005) Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification. Nat Neurosci 8: 279-287.[CrossRef][Medline]

Riven I, Kalmanzon E, Segev L, and Reuveny E (2003) Conformational rearrangements associated with the gating of the G protein-coupled potassium channel revealed by FRET microscopy. Neuron 38: 225-235.[CrossRef][Medline]

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