Molecular pharmacology and therapeutic potential of neuronal Kv7-modulating drugs

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The Kv7 potassium channel family encompasses five members (from Kv7.1 to Kv7.5) having distinct expression pattern and functional role. Although Kv7.1 is prevalently expressed in the cardiac muscle, Kv7.2, Kv7.3, Kv7.4, and Kv7.5 are expressed in neural tissue. Mutations in Kv7.2 and/or Kv7.3 genes are responsible for an autosomal-dominant epilepsy of the newborn defined as benign familial neonatal seizures (BFNS), whereas defects in the Kv7.4 gene have been found in families affected by a rare form of nonsyndromic autosomal-dominant hearing loss (DFNA2). Compounds acting as direct activators of neuronal channels formed by Kv7 subunits have been approved for clinical use as analgesics or are in advanced stages of clinical evaluation as anticonvulsants; in addition to these indications, solid preclinical studies reveal their potential usefulness in other diseases characterized by neuronal hyperexcitability. In the present work, we will summarize the available evidence providing proof-of-principles that neuronal Kv7 channels are highly attractive pharmacological targets, review the molecular basis of their peculiar pharmacological sensitivity, introduce some newly synthesized IKM openers showing improved pharmacokinetic or pharmacodynamic properties compared to older congeners, and discuss the potential novel therapeutic application of neuronal Kv7 channels in diseases additional to epilepsy.

Section snippets

The M-current: functional role, molecular identification, and regulation

Potassium (K+) currents with distinct subcellular localization, biophysical properties, modulation, and pharmacological profile are primary regulators of intrinsic electrical properties of neurons and their responsiveness to synaptic inputs [1]; an increase in membrane conductance to K+ ions causes neuronal hyperpolarization and reduces firing frequency, exerting a strong inhibitory function on neuronal excitability.

Among voltage-gated K+ currents, the M-current (IKM) is a primary transducer of

Human diseases and animal models of neuronal Kv7 genes dysfunction

Neuronal Kv7 gene defects have been implicated in two rare forms of genetically-determined human channelopathies, namely benign familial neonatal seizures (BFNS) and nonsyndromic autosomal-dominant hearing loss (DFNA2).

BFNS is a rare autosomal-dominant idiopathic epilepsy of the newborn, characterized by the occurrence of focal convulsions starting around the third day of postnatal life and spontaneously disappearing after few weeks or months; mutation in either Kv7.2 [29•, 30•] or Kv7.3 [31]

Pharmacological modulation of neuronal Kv7 channels

Given the previously mentioned functional and genetic evidence, it is perhaps not too surprising that neuronal Kv7 channels are currently considered primary pharmacological targets for a number of human diseases. Academic and industrial efforts are currently being pursued to synthesize novel chemical entities to interfere with Kv7 channels, or to test the involvement of specific Kv7 genes in novel diseases. Compounds acting either as blockers or as activators of IKM have often been developed

The binding site for neuronal Kv7 activators

As previously mentioned, IKM openers act by an unusual molecular mechanism, namely by stabilizing the open configuration of Kv7 channels; therefore, the identification of the target sites on the channel molecule might serve as a starting point for structure–activity efforts directed toward the identification of compounds able to discriminate among channels formed by distinct Kv7 subunits, possibly contributing to the development of more specific, more effective, and less toxic Kv7 modulators.

Conclusions

Few examples can illustrate better than the recent history of IKM and IKM modulators how major scientific achievements derive from the convergence of results from often unrelated fields. It is astonishing how efforts from human genetics, physiology, pharmacology, and pharmaceutical chemistry have perhaps unexpectedly merged together to generate significant advancements in the identification of the molecular pathogenesis of human epilepsies and sensory disorders, of a novel molecular mechanism

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

Note added in proof

While the present manuscript was in preparation, a paper has been published (Xiong Q, Sun H, Li M: Zinc pyrithione-mediated activation of voltage-gated KCNQ potassium channels rescues epileptogenic mutants. Nature Chem Biol 2007, 3:287–296) reporting the identification of a new opener, zinc pyrithione (ZnPy), which activates both recombinant KCNQs and native IKM currents. In recombinant KCNQ2 channels, ZnPy produces both an hyperpolarizing gating shift and an increase in the maximal

Acknowledgements

The authors would like to acknowledge the work of past and present collaborators, as well as to apologize to those whose work has not been cited because of space limitations. The present study was supported by grants from Telethon GP07125, the Italian Ministry of Health (Progetto Doping 2005), and the European Commission STREP no. 503038 to MT.

References (78)

  • C. Biervert et al.

    A potassium channel mutation in neonatal human epilepsy

    Science

    (1998)
  • Y. Yang et al.

    Spontaneous deletion of epilepsy gene orthologs in a mutant mouse with a low electroconvulsive threshold

    Hum Mol Genet

    (2003)
  • L. Tatulian et al.

    Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine

    J Neurosci

    (2001)
  • R.J. Porter et al.

    Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures

    Neurology

    (2007)
  • A. Peretz et al.

    Meclofenamic acid and diclofenac, novel templates of KCNQ2/Q3 potassium channel openers, depress cortical neuron activity and exhibit anticonvulsant properties

    Mol Pharmacol

    (2005)
  • Y.J. Wu et al.

    (S)-N-[1-(4-Cyclopropylmethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethyl]-3-(2-fluoro-phenyl)-acrylamide is a potent and efficacious KCNQ2 opener which inhibits induced hyperexcitability of rat hippocampal neurons

    Bioorg Med Chem Lett

    (2004)
  • T.V. Wuttke et al.

    The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate

    Mol Pharmacol

    (2005)
  • A. Schenzer et al.

    Molecular determinants of KCNQ (Kv7) K+ channel sensitivity to the anticonvulsant retigabine

    J Neurosci

    (2005)
  • A.N. Nielsen et al.

    Pharmacological characterisation of acid-induced muscle allodynia in rats

    Eur J Pharmacol

    (2004)
  • N.N. Osborne et al.

    Protection of rabbit retina from ischemic injury by flupirtine

    Invest Ophthalmol Vis Sci

    (1996)
  • F. Block et al.

    Flupirtine protects against ischaemic retinal dysfunction in rats

    Neuroreport

    (1994)
  • H.H. Hansen et al.

    The neuronal KCNQ channel opener retigabine inhibits locomotor activity and reduces forebrain excitatory responses to the psychostimulants cocaine, methylphenidate and phencyclidine

    Eur J Pharmacol

    (2007)
  • C.C. Shieh et al.

    Potassium channels: molecular defects, diseases, and therapeutic opportunities

    Pharmacol Rev

    (2000)
  • D.A. Brown et al.

    Muscarinic suppression of a novel voltage sensitive K+ current in a vertebrate neurone

    Nature

    (1980)
  • N.V. Marrion

    Control of M-current

    Annu Rev Physiol

    (1997)
  • P. Delmas et al.

    Pathways modulating neural KCNQ/M (Kv7) potassium channels

    Nat Rev Neurosci

    (2005)
  • E.C. Cooper et al.

    Colocalization and coassembly of two human brain M-type potassium channel subunits that are mutated in epilepsy

    Proc Natl Acad Sci U S A

    (2000)
  • E.C. Cooper et al.

    M channel KCNQ2 subunits are localized to key sites for control of neuronal network oscillations and synchronization in mouse brain

    J Neurosci

    (2001)
  • J.J. Devaux et al.

    KCNQ2 is a nodal K+ channel

    J Neurosci

    (2004)
  • Z. Pan et al.

    A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon

    J Neurosci

    (2006)
  • M. Martire et al.

    M channels containing KCNQ2 subunits modulate norepinephrine, aspartate, and GABA release from hippocampal nerve terminals

    J Neurosci

    (2004)
  • M. Martire et al.

    Involvement of KCNQ2 subunits in [3H]dopamine release triggered by depolarization and pre-synaptic muscarinic receptor activation from rat striatal synaptosomes

    J Neurochem

    (2007)
  • H.S. Wang et al.

    KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel

    Science

    (1998)
  • Q. Wang et al.

    Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias

    Nat Genet

    (1996)
  • C. Kubisch et al.

    KCNQ4, a novel potassium channel expressed in sensory outer cells, is mutated in dominant deafness

    Cell

    (1999)
  • T. Kharkovets et al.

    KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway

    Proc Natl Acad Sci U S A

    (2000)
  • S.Y. Yeung et al.

    Molecular expression and pharmacological identification of a role for K(v)7 channels in murine vascular reactivity

    Br J Pharmacol

    (2007)
  • M. Schwake et al.

    Surface expression and single channel properties of KCNQ2/KCNQ3, M-type K+ channels involved in epilepsy

    J Biol Chem

    (2000)
  • M.V. Soldovieri et al.

    Decreased subunit stability as a novel mechanism for potassium current impairment by a KCNQ2 C-terminus mutation causing benign familial neonatal convulsion

    J Biol Chem

    (2006)
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