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International Union of Pharmacology. XLI. Compendium of Voltage-Gated Ion Channels: Potassium Channels

Department of Microbiology and Molecular Genetics, University of California-Irvine, Irvine, California (G.A.G.); Department of Physiology and Biophysics, University of California-Irvine, Irvine, California (K.G.C.); Vollum Institute, Oregon Health Sciences University, Portland, Oregon (J.P.A.); Merck Research Laboratories, San Diego, California (J.A.); Department of Pharmacology, University of Virginia Health System, Charlottesville, Virginia (D.A.B.); Howard Hughes Medical Institute, Children's Hospital, Harvard Medical School, Boston, Massachusetts (D.E.C.); Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania (M.C.); Department of Medicine, Section of Nephrology, Yale University School of Medicine, West Haven Veterans Affairs Medical Center, New Haven, Connecticut (G.V.D.); Molecular Medicine Laboratory, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., Tsukuba-shi, Ibaraki, Japan (K.F.); 4120 Genetics, University of Wisconsin Medical School, Madison, Wisconsin (B.G.); Department of Biochemistry and Biophysics, Merck Research Laboratories, Rahway, New Jersey (M.L.G.); Department of Applied Physiology, University Ulm, Ulm, Germany (S.G.); 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 Physiology, Finch University of Health Sciences, The Chicago Medical School, Chicago, Illinois (D.K.); Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee (S.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, Valbonne, France (M.L.); Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France (F.L.); Division of Biology, California Institute of Technology, Pasadena, California (H.A.L.); Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, New York (D.M.); Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri (C.G.N.); Pediatrics and Cellular and Molecular Physiology, Yale University School of Medicine, Boyer Center for Molecular Medicine, New Haven, Connecticut (I.O.); Sensory Function Group, Centre for Neuroscience Research, King's College, London, United Kingdom (J.R.); Department of Physiology, University of Wisconsin-Madison, Madison, Wisconsin (G.A.R.); Departments of Physiology, Neuroscience, and Biochemistry, New York University School of Medicine, New York, New York (B.R.); Eccles Institute of Human Genetics, University of Utah, Salt Lake City, Utah (M.S.); Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chuo-ku Chiba, Japan (S.S.); MPI fuer experimentelle Medizin, Abt. Molekulare Biologie Neuronaler Signale, Goettingen, Germany (W.S.); Department of Biomedical Sciences, Colorado State University, Ft. Collins, Colorado (M.M.T.); Department of Molecular, Cellular and Developmental Biology, and Neuroscience Research Institute, University of California-Santa Barbara, Santa Barbara, California (C.A.V.); Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri (A.W.); Department of Physiology and Biophysics, University of California-Irvine, Irvine, California (H.W.); and Department of Biology, University of Tulsa, Tulsa, Oklahoma (R.S.W.)

Abstract

Structural Characteristics

Human Gene Nomenclature Committee System

The Standardized K+ Channel Nomenclature System

Formulation of a Rational Classification

	Abstract

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Almost a decade ago, a standardized nomenclature for the six-transmembrane domain (TM), voltage-gated K⁺ channel genes—the K_V naming system—was widely adopted (Chandy et al., 1991; Gutman and Chandy, 1993). This nomenclature was based on deduced phylogenetic relationships; channels that shared 65% sequence identity being assigned to one subfamily. A parallel nomenclature—KCN—was developed by the Human Genome Organisation (HUGO) (White et al., 1997). Since then, the K⁺ channel superfamily of genes has greatly expanded, requiring an update of the naming system.

	Structural Characteristics

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Several structural classes of the potassium channels are now known, as illustrated by the transmembrane folding diagrams for this section of the Compendium, and most of these classes have multiple members.

The 6TM proteins include the K_V channels, and the related small-conductance and intermediate-conductance Ca²⁺-activated K⁺ channels (K_Ca). Both the N and C termini of these proteins are located intracellularly, and the region between the fifth and sixth transmembrane domains (the P region) forms the ion conduction pathway. The functional channel is formed by the tetrameric association of these 6TM/1P subunits.

The second class of 2TM proteins includes the inward rectifiers, the K_ATP channels and the G protein-coupled channels (Doupnik et al., 1995). The N and C termini of these channels are also located cytoplasmically, the P region between the two transmembrane domains forms the pore, and the functional channel is a tetramer of these 2TM/1P subunits.

A third class has 7TM and encodes the large-conductance channel, Slo. There is a P region between TMVI and TMVII, and the channel functions as a tetramer, but unlike the other channels, Slo has its N terminus located extracellularly.

A fourth class of proteins has a 6TM/1P segment linked in tandem to a 2TM/1P segment, and the functional channel in this case is formed from the dimeric association of the 8TM/2P subunit.

Yet another class of channels, the K_2P family, contains two 2TM/1P region-containing subunits linked in tandem, and the functional channel is a dimer of the 4TM/2P subunits.

	Human Gene Nomenclature Committee System

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The KCN system established by the Human Gene Nomenclature Committee (HGNC) of HUGO (Table 1) suffers from a lack of any rational basis for nomenclature and, in particular, ignores the structural and phylogenetic relationships of these proteins. For example, the KCNA–KCND subfamilies refer to 6TM/1P proteins, whereas the KCNE subfamily corresponds to an unrelated protein that functions as an accessory subunit to some families of K⁺ channels. Subfamilies encoding other 6TM/1P proteins include KCNF, KCNG, KCNH, KCNN, KCNQ, and KCNS, whereas KCNJ contains the 2TM/1P proteins, the KCNK subfamily corresponds to the 4TM/2P proteins, and the 7TM/1P is subfamily KCNMA1. Even though the Eag, Erg, and Elk channels are very different in their sequences, they are grouped together as KCNH; several members of this group, namely Elk1, Erg2, and Erg3, have not yet been assigned HGNC names. Similarly, the small-conductance (SKCa1–SKCa3) and intermediate-conductance (IKCa1) Ca²⁺-activated K⁺ channels are grouped together in the KCNN subfamily even though they share only 45% amino acid sequence identity and therefore are best considered as belonging to distinct subfamilies.

	The Standardized K+ Channel Nomenclature System

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The original K_V nomenclature that created subfamilies K_V1–K_V6 has not been updated for several years. As new genes were discovered the name K_V7 was skipped, and these new genes were instead assigned to subfamilies K_V8 and K_V9. Also, the more recently discovered KCNH (Eag, Erg, Elk) and KCNQ (KVLQT) subfamilies have not been included in the K_V classification. A standardized nomenclature has been adopted in the case of the 2TM/1P channels, and subfamilies defined in this K_ir family determined by the degree of sequence relatedness.

	Formulation of a Rational Classification

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With the completion of the mapping of the human genome, the time may be ripe for a re-evaluation of these issues, and the development of a uniform and rational nomenclature for all K⁺-selective channels. Such a naming system could incorporate the architectural similarities between different channel families, as well as their phylogenetic relationships. For example, the numerous 6TM/1P proteins and the sole 7TM/1P channel listed in Table 1 could be grouped into a single large family comprising multiple subfamilies defined according to their phylogenetic relatedness. Similarly, the 2TM/1P channels and the 2P channels could each be clustered into a separate family containing multiple subfamilies.

The standardized nomenclature for potassium channels presented in this compendium is shown in the phylogenetic trees of Figs. 1 through 4. The 6TM/1P channels have been organized into two distinct groups based on their structural relatedness and predominant functional characteristics, namely the voltage-gated (K_V) and calcium-activated (K_Ca) channels. The two-pore (K_2P) and inward rectifier (K_ir) channels likewise form two additional groups. Figure 1a shows the voltage-gated K⁺ channels of families K_V1–K_V6 and K_V8–K_V9, in a phylogenetic reconstruction using maximum parsimony based on an amino acid sequence alignment. Among this group, only K_V1.8 currently lacks an HGNC name. The five members of a second K_V group, the K_V7 family (KCNQ1–KCNQ5), cannot readily be aligned with other K_V channel proteins and are therefore shown in a separate tree in Fig. 1b. The three remaining K_V families, K_V10, K_V11 and K_V12, are closely enough related to each other to be shown in the single tree of Fig. 1c.

View larger version (24K): [in this window] [in a new window]   FIG. 1. Phylogenetic trees of the KV channels. a, the KV1–KV6 and KV8–KV9 families; b, the KV7 family; c, the KV10–KV12 families. An amino acid sequence alignment made using CLUSTAL W was subjected to analysis by maximum parsimony (PAUP*). Only the hydrophobic core region of the alignment was used for analysis.

View larger version (21K): [in this window] [in a new window]   FIG. 2. Two phylogenetic trees showing the KCa1–KCa5 families. See Fig. 1 for details of analysis.

View larger version (33K): [in this window] [in a new window]   FIG. 3. Phylogenetic tree showing the K2P families. See Fig. 1 for details of analysis.

View larger version (33K): [in this window] [in a new window]   FIG. 4. Phylogenetic tree showing the Kir families. See Fig. 1 for details of analysis.

The five families comprising the calcium-sensitive potassium channels, K_Ca1–K_Ca5, numbered according to the order of their discovery, are shown in the two trees of Fig. 2. The phylogenetic relationship between the K_Ca1, K_Ca4, K_Ca5 group on the one hand, and the K_Ca2, K_Ca3 group on the other, is insufficiently clear at this time to readily connect them into a single tree.

The two-pore or K_2P potassium channels are shown in the tree of Fig. 3. The numbers have been taken from the HGNC "KCNK" numbering, without resequencing around the missing numbers (namely 8, 11, and 14), and without consolidating clearly related channels into subfamilies. A consensus among researchers in the field will hopefully establish a more rational nomenclature in the future.

The last remaining group of potassium channels, the inward rectifier or K_ir channels, is represented in the tree of Fig. 4, using the previously established nomenclature and subfamily groupings.

	Footnotes

 
Address correspondence to: Dr. George A. Gutman, Department of Microbiology and Molecular Genetics, or Dr. K. George Chandy, Department of Physiology and Biophysics, University of California-Irvine, Irvine, CA, 92697. E-mail: gagutman{at}uci.edu and gchandy{at}uci.edu

DOI: 10.1124/pr.55.4.9.

¹ This work was previously published in Catterall WA, Chandy KG, and Gutman GA, eds. (2002) The IUPHAR Compendium of Voltage-Gated Ion Channels, International Union of Pharmacology Media, Leeds, UK.

	References

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Chandy KG, Douglas J, Gutman GA, Jan L, Joho R, Kaczmarek L, McKinnon D, North RA, Numa S, Philipson L, et al. (1991) A simplified gene nomenclature. Nature (Lond) 352: 26.[Medline]

Doupnik CA, Davidson N, and Lester HA (1995) The inward rectifier potassium channel family. Curr Opin Neurobiol 5: 268-277.[CrossRef][Medline]

Gutman GA and Chandy KG (1993) Nomenclature for vertebrate voltage-gated K⁺ channels. Sem Neurosci 5: 101-106.

White JA, McAlpine PJ, Antonarakis S, Cann H, Eppig JT, Frazer K, Frezal J, Lancet D, Nahmias J, Pearson P, et al. (1997) Guidelines for human gene nomenclature. Genomics 45: 468-471.[CrossRef][Medline]

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This Article Abstract Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gutman, G. A. Articles by Wymore, R. S. Search for Related Content PubMed PubMed Citation Articles by Gutman, G. A. Articles by Wymore, R. S.