Potassium ion channels and human disease: phenotypes to drug targets?

https://doi.org/10.1016/S0958-1669(98)80133-XGet rights and content

Abstract

A significant difficulty faced by the pharmaceutical industry is the initial identification and selection of macromolecular targets upon which de novo drug discovery programs can be initiated. A drug target should have several characteristics: known biological function; robust assay systems for in vitro characterization and high-throughput screening; and be specifically modified by and accessible to small molecular weight compounds in vivo. Ion channels have many of these attributes and can be viewed as suitable targets for small molecule drugs. Potassium (K+) ion channels form a large and diverse gene family responsible for critical functions in numerous cell types, tissues and organs. Recent discoveries, facilitated by genomics technologies combined with advanced biophysical characterization methods, have identified novel K+ channels that are involved in important physiologic processes, or mutated in human inherited disease. These findings, coupled with a rapidly growing body of information regarding modulatory channel subunits and high resolution channel structures, are providing the critical information necessary for validation of K+ channels as drug targets.

References (97)

  • CA Doupnik et al.

    The inward rectifier potassium channel family

    Curr Opin Neurobiol

    (1995)
  • S Corey et al.

    Number and stoichiometry of subunits in the native atrial G-protein-gated K+ channel, IKACh

    J Biol Chem

    (1998)
  • B Santoro et al.

    Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain

    Cell

    (1998)
  • K Ho et al.

    Cloning and expression of an inwardly rectifying ATP-regulated potassium channel

    Nature

    (1993)
  • ME Shuck et al.

    Cloning and characterization of multiple forms of the human kidney ROM-K potassium channel

    J Biol Chem

    (1994)
  • A Nestorowicz et al.

    A nonsense mutation in the inward rectifier potassium channel gene, Klr6.2, is associated with familial hyperinsulinism

    Diabetes

    (1997)
  • XJ Yuan et al.

    Molecular basis and function of voltage-gated K+ channels in pulmonary arterial smooth muscle cells

    Am J Physiol

    (1998)
  • ON Osipenko et al.

    Regulation of the resting potential of rabbit pulmonary artery myocytes by a low threshold, O2-sensing potassium current

    Br J Pharmacol

    (1997)
  • PA Slesinger et al.

    Functional effects of the mouse weaver mutation on G protein-gated inwardly rectifying K+ channels

    Neuron

    (1996)
  • B Hille
  • LY Jan et al.

    Cloned potassium channels from eukaryotes and prokaryotes

    Ann Rev Neurosci

    (1997)
  • DM Papazian et al.

    Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila

    Science

    (1987)
  • BL Tempel et al.

    Sequence of a probable potassium channel component encoded at Shaker locus of Drosophila

    Science

    (1987)
  • LE Iverson et al.

    A-type potassium channels expressed from Shaker locus cDNA

    Proc Natl Acad Sci USA

    (1988)
  • O Pongs et al.

    Shaker encodes a family of putative potassium channel proteins in the nervous system of Drosophila

    EMBO J

    (1988)
  • B Ganetzky et al.

    New potassium gene families in flies and mammals: from mutants to molecules

  • R MacKinnon

    Determination of the subunit stoichiometry of a voltage-activated potassium channel

    Nature

    (1991)
  • J Yang et al.

    Determination of the subunit stoichiometry of an inwardly rectifying potassium channel

    Neuron

    (1995)
  • DA Doyle et al.

    The structure of the potassium channel: molecular basis of K+ conduction and selectivity

    Science

    (1998)
  • SA Goldstein et al.

    Sequence and function of the two P domain potassium channels: implications of an emerging superfamily

    J Mol Med

    (1998)
  • KA Ketchum et al.

    A new family of outwardly rectifying potassium channel proteins with two pore domains in tandem

    Nature

    (1995)
  • SA Goldstein et al.

    ORK1, a potassium-selective leak channel with two pore domains cloned from Drosophila melanogaster by expression in Saccharomyces cerevisiae

    Proc Natl Acad Sci USA

    (1996)
  • F Lesage et al.

    TWIK-1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure

    EMBO J

    (1996)
  • F Duprat et al.

    TASK, a human background K+ channel to sense external pH variations near physiological pH

    EMBO J

    (1997)
  • M Fink et al.

    A neuronal two P domain K+ channel stimulated by arachidonic acid and polyunsaturated fatty acids

    EMBO J

    (1998)
  • D Leonoudakis et al.

    An open rectifier potassium channel with two pore domains in tandem cloned from rat cerebellum

    J Neurosci

    (1998)
  • J Xu et al.

    Distinct functional stoichiometry of potassium channel beta subunits

    Proc Natl Acad Sci USA

    (1998)
  • J Xu et al.

    Auxiliary subunits of Shaker-type potassium channels

    Trends Cardiol Med

    (1998)
  • LK Kaczmarek et al.

    Properties and regulation of the minK potassium channel protein

    Physiol Rev

    (1997)
  • SW Chouinard et al.

    A potassium channel beta subunit related to the aldo-keto reductase superfamily is encoded by the Drosophila hyperkinetic locus

    Proc Natl Acad Sci USA

    (1995)
  • N Inagaki et al.

    A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels

    Neuron

    (1996)
  • DE Bulman

    Phenotype variation and newcomers in ion channel disorders

    Hum Mol Genet

    (1997)
  • MJ Ackerman et al.

    Ion channels: basic science and clinical disease

    N Engl J Med

    (1997)
  • MC Sanguinetti et al.

    Potassium channelopathies

    Neuropharmacol

    (1997)
  • MC Sanguinetti

    Potassium channels of cardiac myocytes

    Methods Neurosci

    (1994)
  • RC Kass et al.

    Potassium channels in the heart. Cellular, molecular and clinical implications

    Trends Cardiovasc Med

    (1993)
  • ME Curran et al.

    A molecular basis for cardiac arrhythmia: HERG mutations cause Long QT syndrome

    Cell

    (1995)
  • MC Sanguinetti et al.

    A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERB encodes the IKr potassium channel

    Cell

    (1995)
  • Cited by (41)

    • Localization and Targeting of GIRK Channels in Mammalian Central Neurons

      2015, International Review of Neurobiology
      Citation Excerpt :

      Ion channels are classified by their gating properties and ion selectivity for Na+, Ca2 +, Cl−, and K+ (Hille, 2001). Potassium (K+)-selective channels are key determinants of membrane excitability and regulate a variety of cellular processes including membrane potential, signal transduction, hormone release, vascular tone, cell volume, and immune responses (Curran, 1998). Four different subfamilies of K+ channels have been proposed based on their structural and phylogenetic relationship: voltage-gated K+ (Kv) channels, Ca2 +-activated K+ (KCa) channels, two-pore K+ (K2P) channels, and inwardly rectifying (Kir) channels (Gutman et al., 2005).

    • A cell-based impedance assay for monitoring transient receptor potential (TRP) ion channel activity

      2011, Biosensors and Bioelectronics
      Citation Excerpt :

      The applied microelectrodes are often non-transparent and do not allow microscopic imaging of the adherent cells. Ion channel characterisation using cell-based impedance spectroscopy is rarely found in the literature, although ion channels located in cell membranes have crucial roles in physiology and pathophysiology and are important targets for drug discovery (Curran, 1998; Wissenbach et al., 2004; Okuhara et al., 2007; Jegla et al., 2009; Patapoutian et al., 2009; Mathie, 2010; Nassini et al., 2010). Impedimetric single cell analysis of ion channel activity in bovine chromaffin cells might serve as a rare example (Han and Frazier, 2006) where the observed impedance changes could be directly attributed to a molecular compound within the cell membrane.

    • Cloning and characterization of BmK86, a novel K<sup>+</sup>-channel blocker from scorpion venom

      2007, Biochemical and Biophysical Research Communications
      Citation Excerpt :

      K+ channels play a key role in cellular excitability and signal transduction. Exploring their structure and function has led to the design of many therapeutic compounds [23,24]. To obtain yet more useful tools for K+-channel studies, it is important to continue the search for new and specific toxins.

    View all citing articles on Scopus
    View full text