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(253), Re15. [DOI: 10.1126/Stke.2532004Re15] 2004 The VGL-Chanome: A Protein Superfamily Specialized for Electrical Signaling and Ionic Homeostasis Frank H. Yu and William A. Catterall (5 October 2004) Sci. STKE 2004 (253), re15. [DOI: 10.1126/stke.2532004re15] The following resources related to this article are available online at http://stke.sciencemag.org. This information is current as of 7 July 2009. Article Tools Visit the online version of this article to access the personalization and article tools: http://stke.sciencemag.org/cgi/content/full/sigtrans;2004/253/re15 Supplemental "Supplementary Table 1" Materials http://stke.sciencemag.org/cgi/content/full/sigtrans;2004/253/re15/DC1 Related Content The editors suggest related resources on Science's sites: http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2006/360/tw376 http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2006/350/pe33 http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2006/333/tw149 http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2005/307/pe50 http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2005/302/pe46 Downloaded from http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2005/270/tw55 http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2004/233/pe22 http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2004/233/pe23 http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2004/227/pe16 http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2004/219/re4 http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2003/194/pe32 http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2003/188/re10 http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2002/123/pe12 stke.sciencemag.org http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2001/111/re19 http://stke.sciencemag.org/cgi/content/abstract/sigtrans;2001/90/re1 References This article has been cited by 13 article(s) hosted by HighWire Press; see: http://stke.sciencemag.org/cgi/content/full/sigtrans;2004/253/re15#BIBL This article cites 217 articles, 78 of which can be accessed for free: http://stke.sciencemag.org/cgi/content/full/sigtrans;2004/253/re15#otherarticles on July 7, 2009 Glossary Look up definitions for abbreviations and terms found in this article: http://stke.sciencemag.org/glossary/ Permissions Obtain information about reproducing this article: http://www.sciencemag.org/about/permissions.dtl Science's STKE (ISSN 1525-8882) was published from September 1999 through December 2007 by the American Association for the Advancement of Science; 1200 New York Avenue, NW, Washington, DC 20005. Copyright 2008 by the American Association for the Advancement of Science; all rights reserved. The journal continues under the title Science Signaling (ISSN 1937-9145) starting January 2008. The title Science's STKE is a registered trademark of the American Association for the Advancement of Science. R EVIEW The VGL-Chanome: A Protein Superfamily Specialized for Electrical Signaling and Ionic Homeostasis Frank H. Yu1 and William A. Catterall1* (Published 5 October 2004) Complex multicellular organisms require rapid and voltage-gated ion channel protein superfamily (Fig. 1) (1). This accurate transmission of information among cells protein superfamily of 143 members is one of the largest groups and tissues and tight coordination of distant of signal transduction proteins, ranking third after the G pro- functions. Electrical signals and resulting intracellu- tein–coupled receptors and the protein kinases in number. In lar calcium transients, in vertebrates, control con- analogy to the term “kinome” introduced for the protein kinase traction of muscle, secretion of hormones, sensation superfamily (2), we propose the term “chanome” for the of the environment, processing of information in the universe of ion channel proteins and the VGL-chanome for the brain, and output from the brain to peripheral superfamily of voltage-gated and related cation channels: the tissues. In nonexcitable cells, calcium transients sig- voltage-gated–like ion channels. Other large groups of ion nal many key cellular events, including secretion, channels, such as the ligand-gated ion channels and chloride Downloaded from gene expression, and cell division. In epithelial cells, channels, might be referred to by similar shorthand names such huge ion fluxes are conducted across tissue bound- as LG-chanome and Cl-chanome. Here we review the molecular aries. All of these physiological processes are medi- and evolutionary relations among the members of the VGL- ated in part by members of the voltage-gated ion chanome and describe their functional roles in cell physiology. channel protein superfamily. This protein superfami- ly of 143 members is one of the largest groups of Structural and Functional Motifs signal transduction proteins, ranking third after the The architectures of the ion channel families consist of four stke.sciencemag.org G protein–coupled receptors and the protein kinases variations built on a common pore-forming structural theme. in number. Each member of this superfamily con- The founding members of this superfamily are the voltage- tains a similar pore structure, usually covalently at- gated sodium channels (Fig. 1, NaV) (3–6). Their principal α tached to regulatory domains that respond to subunits are composed of four homologous domains (I to IV) changes in membrane voltage, intracellular signaling that form the common structural motif for this family (7, 8) molecules, or both. Eight families are included in this (Fig. 2A). Each of these domains contains six regions that are protein superfamily—voltage-gated sodium, calcium, thought to form membrane-spanning α helices (termed seg- and potassium channels; calcium-activated potassi- ments S1 to S6) and a membrane-reentrant loop between the S5 on July 7, 2009 um channels; cyclic nucleotide–modulated ion chan- and S6 segments (9). Structural analysis by high-resolution EM nels; transient receptor potential (TRP) channels; in- and image reconstruction shows that the four homologous do- wardly rectifying potassium channels; and two-pore mains surround a central pore and suggests laterally oriented potassium channels. This article identifies all of the entry ports in each domain for ion transit toward the central members of this protein superfamily in the human pore (10) (Fig. 2A). Voltage-gated calcium (CaV) channels have genome, reviews the molecular and evolutionary re- a similar structure (see below). Voltage-gated potassium lations among these ion channels, and describes channels, first identified as the product of the gene encoding their functional roles in cell physiology. the Shaker mutation in the fruit fly Drosophila, exemplify the second architectural theme in the ion channel superfamily. They Introduction are composed of tetramers of α subunits that each resemble one Complex multicellular organisms require rapid and accurate homologous domain of sodium and calcium channels (Fig. 1, transmission of information among cells and tissues and tight KV) (11–13). Several other families of ion channels also have coordination of distant functions. Electrical signals and the re- this tetrameric architecture (Fig. 1; see below). The inwardly sulting intracellular calcium transients, in vertebrates, control rectifying potassium channels constitute the simplest structural contraction of muscle, secretion of hormones, sensation of the motif in the ion channel protein superfamily. These channels are environment, processing of information in the brain, and output complexes of four subunits that each have only two transmem- from the brain to peripheral tissues. In nonexcitable cells, calci- brane segments, termed M1 and M2, which are analogous in um transients signal many key cellular events, including secre- structure and function to the S5 and S6 segments of voltage- tion, gene expression, and cell division. In epithelial cells, huge gated sodium, calcium, and potassium channels (Fig. 1, Kir) ion fluxes are conducted across tissue boundaries. All of these (14, 15). Two of these pore motifs are linked together to gener- physiological processes are mediated in part by members of the ate the fourth structural architecture, the two-pore potassium channels (Fig. 1, K2P) (16, 17). 1Department of Pharmacology, Mailstop 357280, University of Wash- The functional elements of the ion channel family of proteins can ington, Seattle, WA 98195–7280, USA. be divided into three complementary aspects: ion conductance, pore *Corresponding author. E-mail: [email protected]. gating, and regulation. The ion-conducting pore and selectivity filter www.stke.org/cgi/content/full/sigtrans;2004/253/re15 Page 1 R EVIEW R CNG HCN Cav Kv10-12 Nav K2p TPC Downloaded from TRP stke.sciencemag.org Kv1-9 on July 7, 2009 R 0.05 substitutions/site KCa Kir Fig. 1. Representation of the amino acid sequence relations of the minimal pore regions of the voltage-gated ion channel superfamily. This global view of the 143 members of the structurally related ion channel genes highlights seven groups of ion channel families and their mem- brane topologies. Four-domain channels (CaV and NaV) are shown as blue branches, potassium selective channels are shown as red branch- es, cyclic nucleotide–gated channels are shown as magenta branches, and transient receptor potential (TRP) and related channels are shown as green branches. Background colors separate the ion channel proteins into related groups: light blue, CaV and NaV ; light green, TRP chan- nels; light red, potassium channels, except KV10–12, which have a cyclic nucleotide–binding domain and are more closely related to CNG and HCN channels; light orange, KV10–12 channels and cyclic nucleotide–modulated CNG and HCN channels. Minimal pore regions bounded by the transmembrane segments M1 or S5 and M2 or S6 were aligned by Clustal X (221) and refined manually for the 143 ion channel members (Appendix); amino acid sequence positions with gaps in the alignment were omitted from the analyses. The pore regions of the fourth homolo- gous domain of NaV and CaV channels, the second domain of TPC, and the first pore regions of the K2P channels were used to assemble the alignment. This unrooted consensus tree was built by minimum evolution analysis using PAUP v.
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