Molecular pharmacology and therapeutic potential of neuronal Kv7-modulating drugs
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.
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2021, European Journal of PharmacologyCitation Excerpt :In 2011, the drug retigabine (RTG) passed the clinical trials as the first approved KV7 channel opener for human use. The most studied modulator of KV7 channels, RTG has a novel binding site and mechanism of action for activating the KV7.2-5 channels, but not the related cardiac KCNQ1 subunit (Table 1) (Gunthorpe et al., 2012; Miceli et al., 2008; Tatulian et al., 2001; Wuttke et al., 2005). RTG has effects on a range of seizure disorders, and it has been approved by the FDA as an antiepileptic drug for the treatment of partial/focal seizures (Harris and Murphy, 2011; Stafstrom et al., 2011).
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