Associate editor: M.A. Rogawski
K+ channels as therapeutic drug targets

https://doi.org/10.1016/S0163-7258(02)00201-2Get rights and content

Abstract

K+ channels play critical roles in a wide variety of physiological processes, including the regulation of heart rate, muscle contraction, neurotransmitter release, neuronal excitability, insulin secretion, epithelial electrolyte transport, cell volume regulation, and cell proliferation. As such, K+ channels have been recognized as potential therapeutic drug targets for many years. Unfortunately, progress toward identifying selective K+ channel modulators has been severely hampered by the need to use native currents and primary cells in the drug-screening process. Today, however, more than 80 K+ channel and K+ channel-related genes have been identified, and an understanding of the molecular composition of many important native K+ currents has begun to emerge. The identification of these molecular K+ channel drug targets should lead to the discovery of novel drug candidates. A summary of progress is presented.

Introduction

K+ channels have been recognized as potential targets for therapeutic drugs for many years. Unfortunately, progress toward identifying selective K+ channel modulators has been severely hampered by the need to use native currents and primary cells in the drug-screening process. In fact, until quite recently, only ATP-sensitive K+ channels and cardiac-delayed rectifier K+ channels (see 2 K, 6.2 K) have been amenable to the drug discovery process. ATP-sensitive K+ channels, in particularly, have been the focus of intense effort in the pharmaceutical industry over the past two decades, and a large number of ATP-sensitive K+-channel openers and blockers have been described. The fact that ATP-sensitive K+-channel openers were generally referred to as “potassium channel openers” or “KCOs” was perhaps indicative of the complete absence of openers of other classes of K+ channels during most of the 1980s and 1990s. Over the last decade, however, the human genome project, together with an intense cloning effort, has identified more than 80 K+ channel-related genes. This, coupled with progress toward understanding the distribution and contribution of K+ channel genes to native currents, and advances in drug-screening technologies, has made K+ channels increasingly attractive as therapeutic drug targets. K+ channel modulators are no longer restricted to openers and blockers of ATP-sensitive K+ channels. Openers and blockers of many K+ channels have now been described, and currently, several highly potent and selective agents are being evaluated in clinical trials for the treatment of a variety of human diseases.

Section snippets

K+ channel physiology

K+ channels are a ubiquitous family of membrane proteins that play critical roles in a wide variety of physiological processes, including the regulation of heart rate, muscle contraction, neurotransmitter release, neuronal excitability, insulin secretion, epithelial electrolyte transport, cell volume regulation, and cell proliferation. A highly diverse set of K+ channels has evolved in order to serve such a wide variety of roles. Some K+ channels, i.e., voltage-gated K+ (Kv) channels, are

K+ channel classification

Over the past decade, there has been an intense effort to clone and characterize mammalian K+ channels. To date, more than 80 K+ channel-related genes (i.e., pore-forming subunits or modulatory subunits) have been cloned and characterized. A brief summary of K+ channel classification is presented in the following sections.

K+ channel assembly

Of the K+-selective channels, the most structural information is known about Kv channels. Kv channels contain four α-subunits that surround a water-filled, K+-selective pore (MacKinnon, 1991). Kv channels can be formed from four identical α-subunits (homomultimers) or from combinations of two or more different α-subunits (heteromultimers). Only α-subunits from the same subfamily are capable of co-assembling to form heteromultimers, i.e., Kv1.x is capable of forming heterotetrameric channels

Relationship between cloned subunits and native K+ currents

As described in the preceding sections, recent cloning efforts have identified a large and diverse set of K+ channel-related genes. Further diversity is generated by alternative splicing of gene products Schwarz et al., 1988, Luneau et al., 1991, Butler et al., 1993, Yano et al., 1994, England et al., 1995, heteromultimeric assembly of α-subunits and assembly with modulatory β-subunits. Despite the seemingly endless possibilities for channel diversity, a combination of biophysical,

K+ channels, immunosuppression, and cell proliferation

Sustained Ca2+ influx through store-operated, Ca2+-release activated Ca2+ channels (ICRAC) is an important step in the cellular signaling pathway that leads to proliferation in a variety of cell types, including T-lymphocytes, prostate cancer cells, and fibroblasts. K+ channels play an essential role in this process by maintaining a favorable electrical driving force for Ca2+ entry. Accordingly, blockers of these K+ channels may inhibit cell proliferation and may be of potential benefit in

Future directions for therapeutic exploitation of K+ channels

As a result of an impressive effort over the last 15 years, more than 80 K+ channels and K+ channel-related genes have been identified. Heteromeric channel assembly, inclusion of modulatory β-subunits, and alternative splicing of gene products can generate seemingly endless possibilities for channel diversity. Despite this, a combination of biophysical, pharmacological, and genetic approaches has started to provide an understanding of the molecular composition of many important native K+

Acknowledgements

The author would like to thank Dr. Neil Castle, Dr. Douglas Krafte, and Dr. Kay Wagoner for helpful comments during the preparation of the review.

References (411)

  • A.R Blight et al.

    Augmentation by 4-aminopyridine of vestibulospinal free fall responses in chronic spinal-injured cats

    J Neurol Sci

    (1987)
  • R Brenner et al.

    Cloning and functional characterization of novel large conductance calcium-activated potassium channel beta subunits, hKCNMB3 and hKCNMB4

    J Biol Chem

    (2000)
  • C Brugnara

    Therapeutic strategies for prevention of sickle cell dehydration

    Blood Cells Mol Dis

    (2001)
  • C Brugnara et al.

    Ca2+-activated K+ transport in erythrocytes. Comparison of binding and transport inhibition by scorpion toxins

    J Biol Chem

    (1993)
  • J.W Butcher et al.

    Differential effects of apamin on neuronal excitability in the nucleus tractus solitarii of rats studied in vitro

    J Auton Nerv Syst

    (1999)
  • F Cacciapuoti et al.

    Effectiveness of glibenclamide on myocardial ischemic ventricular arrhythmias in non-insulin-dependent diabetes mellitus

    Am J Cardiol

    (1991)
  • M.D Cahalan et al.

    Ion channels in the immune system as targets for immunosuppression

    Curr Opin Biotechnol

    (1997)
  • J Campos Rosa et al.

    Bis-quinolinium cyclophanes: a novel class of potent blockers of the apamin-sensitive Ca2+-activated K+ channel

    Bioorg Med Chem Lett

    (1997)
  • N.A Castle et al.

    Dequalinium, a potent inhibitor of apamin-sensitive K+ channels in hepatocytes and of nicotinic responses in skeletal muscle

    Eur J Pharmacol

    (1993)
  • J.P Clement et al.

    Association and stoichiometry of KATP channel subunits

    Neuron

    (1997)
  • S Corey et al.

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

    J Biol Chem

    (1998)
  • M Covarrubias et al.

    Shaker, Shal, Shab, and Shaw express independent K+ current systems

    Neuron

    (1991)
  • M.E Curran et al.

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

    Cell

    (1995)
  • A.J D'Alonzo et al.

    A comparison between the effects of BMS-180448, a novel K+ channel opener, and cromakalim in rat and dog

    Eur J Pharmacol

    (1995)
  • O Deschaux et al.

    Effect of apamin, a selective blocker of Ca2+-activated K+ channel, on habituation and passive avoidance responses in rats

    Neurosci Lett

    (1997)
  • O Deschaux et al.

    Apamin improves learning in an object recognition task in rats

    Neurosci Lett

    (1997)
  • T.G Dinan et al.

    Neuroleptics decrease calcium-activated potassium conductance in hippocampal pyramidal cells

    Brain Res

    (1987)
  • J.C Dreixler et al.

    Block of rat brain recombinant SK channels by tricyclic antidepressants and related compounds

    Eur J Pharmacol

    (2000)
  • G.W Abbott et al.

    A superfamily of small potassium channel subunits: form and function of the MinK-related peptides (MiRPs)

    Q Rev Biophys

    (1998)
  • R Abrol et al.

    Azimilide dihydrochloride: a new class III anti-arrhythmic agent

    Exp Opin Invest Drugs

    (2000)
  • H Adaniya et al.

    Effects of a novel class III antiarrhythmic agent, E-4031, on reentrant tachycardias in rabbit right atrium

    J Cardiovasc Pharmacol

    (1990)
  • N Agopyan et al.

    Effects of trifluoperazine on synaptically evoked potentials and membrane properties of CA1 pyramidal neurons of the rat hippocampus in situ and in vitro

    Synapse

    (1993)
  • L Aguilar-Bryan et al.

    Toward understanding the assembly and structure of KATP channels

    Physiol Rev

    (1998)
  • S.P Aiken et al.

    Reduction of spike frequency adaptation and blockade of M-current in rat CA1 pyramidal neurons by linopirdine (DuP 996), a neurotransmitter release enhancer

    Br J Pharmacol

    (1995)
  • K.E Andersson

    Clinical pharmacology of potassium channel openers

    Pharmacol Toxicol

    (1992)
  • S.L Archer et al.

    Differential distribution of electrophysiologically distinct myocytes in conduit and resistance arteries determines their response to nitric oxide and hypoxia

    Circ Res

    (1996)
  • S.L Archer et al.

    Molecular identification of the role of voltage-gated K+ channels, Kv1.5 and Kv2.1, in hypoxic pulmonary vasoconstriction and control of resting membrane potential in rat pulmonary artery myocytes

    J Clin Invest

    (1998)
  • N.S Atkinson et al.

    A component of calcium-activated potassium channels encoded by the Drospohila slo locus

    Science

    (1991)
  • B.E Banks et al.

    Apamin blocks certain neurotransmitter-induced increases in potassium permeability

    Nature

    (1979)
  • J Barhanin et al.

    KvLQT1 and IsK (minK) proteins associate to form the IKs cardiac potassium current

    Nature

    (1996)
  • I Baro et al.

    Concomitant activation of Cl and K+ currents by secretory stimulation in human epithelial cells

    J Physiol

    (1994)
  • D.M Barry et al.

    Myocardial potassium channels: electrophysiological and molecular diversity

    Annu Rev Physiol

    (1996)
  • D.K Bartschat et al.

    Calcium-activated potassium channels in isolated presynaptic nerve terminals from rat brain

    J Physiol

    (1985)
  • C Beeton et al.

    Selective blocking of voltage-gated K+ channels improves experimental autoimmune encephalomyelitis and inhibits T cell activation

    J Immunol

    (2001)
  • M.I Behrens et al.

    Possible role of apamin-sensitive K+ channels in myotonic dystrophy

    Muscle Nerve

    (1994)
  • K Bielefeldt et al.

    A calcium-activated potassium channel causes frequency-dependent action-potential failures in a mammalian nerve terminal

    J Neurophysiol

    (1993)
  • K Bielefeldt et al.

    Three potassium channels in rat posterior pituitary nerve terminals

    J Physiol

    (1992)
  • C Biervert et al.

    A potassium channel mutation in neonatal human epilepsy

    Science

    (1998)
  • G.E Billman

    The role of the ATP-sensitive K+ channel in K+ accumulation and cardiac arrhythmias during myocardial ischemia

    Cardiovasc Res

    (1994)
  • G.E Billman et al.

    The effects of the ATP-dependent potassium channel antagonist, glyburide, on coronary blood flow and susceptibility to ventricular fibrillation in unanesthetized dogs

    J Cardiovasc Pharmacol

    (1993)
  • Cited by (149)

    • The endocannabinoids and potassium channels—An updated narrative

      2023, Neurobiology and Physiology of the Endocannabinoid System
    • Potassium viroporins as model systems for understanding eukaryotic ion channel behaviour

      2022, Virus Research
      Citation Excerpt :

      K+ ion channels are present in all living species that serve to transport K+ions across the membrane (Kuo et al., 2005). Additionally, depending upon the electric environment, K+channels modulate neuron excitability, cardiac contraction (Sanguinetti and Tristani-Firouzi, 2006), blood pressure maintenance (Wang et al., 2012), immune function (Cahalan et al., 2001), change in the shape of action potential (Schreiber and Seebohm, 2021), can cause repolarisation of cell, trigger the release of hormones and adapt to stress situations (Piccini et al., 2017), and can determine the timing of action potentials of cells etc. (Wickenden, 2002; Potassium channels 2022) (Fig. 1). The basic structure of K+ion channels include transmembrane helices (TMs) that spans the lipid bilayer membrane.

    View all citing articles on Scopus
    View full text