Summary
Because ion channels are involved in many cellular processes, drugs acting on ion channels have long been used for the treatment of many diseases, especially those affecting electrically excitable tissues. The present review discusses the pharmacology of voltage-gated and neurotransmitter-gated ion channels involved in neurologic diseases, with emphasis on neurologic channelopathies. With the discovery of ion channelopathies, the therapeutic value of many basic drugs targeting ion channels has been confirmed. The understanding of the genotype—phenotype relationship has highlighted possible action mechanisms of other empirically used drugs. Moreover, other ion channels have been pinpointed as potential new drug targets. With regards to therapy of channelopathies, experimental investigations of the intimate drug—channel interactions have demonstrated that channel mutations can either increase or decrease affinity for the drug, modifying its potential therapeutic effect. Together with the discovery of channel gene polymorphisms that may affect drug pharmacodynamics, these findings highlight the need for pharmacogenetic research to allow identification of drugs with more specific effects on channel isoforms or mutants, to increase efficacy and reduce side effects. With a greater understanding of channel genetics, structure, and function, together with the identification of novel primary and secondary channelopathies, the number of ion channel drugs for neurologic channelopathies will increase substantially.
Article PDF
Similar content being viewed by others
References
Ruetsch YA, Böni T, Borgeat A. From cocaine to ropivacaine: the history of local anesthetic drugs. Curr Top Med Chem 2001;1: 175–182.
Gutman GA, Chandy KG, Grissmer S, et al. International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacol Rev 2005;57: 473–508.
Dodson PD, Forsythe ID. Presynaptic K+ channels: electrifying regulators of synaptic terminal excitability. Trends Neurosci 2004; 27: 210–217.
Lehmann-Horn F, Lerche H, Jurkat-Rott K. Skeletal muscle channelopathies: myotonias, periodic paralyses and malignant hyperthermia. In: Stålberg E, editor. Clinical neurophysiology of disorders of muscle and neuromuscular junction, including fatigue. Handbook of Clinical Neurophysiology 2. Boston: Elsevier Science; 2003: 457–483.
Vedeler CA, Antoine JC, Giometto B, et al. Management of paraneoplastic neurological syndromes: report of an EFNS Task Force. Eur J Neurol 2006;13: 682–690.
Coghlan MJ, Carroll WA, Gopalakrishnan M. Recent developments in the biology and medicinal chemistry of potassium channel modulators: update from a decade of progress. J Med Chem 2001; 44: 1627–1653.
Munoz-Caro C, Nino A. The nature of the receptor site for the reversible K+ channel blocking by aminopyridines. Biophys Chem 2002;96: 1–14.
Weisz CJ, Raike RS, Soria-Jasso LE, Hess EJ. Potassium channel blockers inhibit the triggers of attacks in the calcium channel mouse mutant tottering. J Neurosci 2005;25: 4141–4145.
Skeie GO, Apostolski S, Evoli A, et al. Guidelines for the treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol 2006;13: 691–699.
Michelakis E. Anorectic drugs and vascular disease: the role of voltage-gated K+ channels. Vascul Pharmacol 2002;38: 51–59.
Tricarico D, Barbieri M, Mele A, Carbonara G, Conte Camerino D. Carbonic anhydrase inhibitors are specific openers of skeletal muscle BK channel of K+-deficient rats. FASEB J 2004;18: 760–761.
Rogawski MA. Diverse mechanisms of antiepileptic drugs in the development pipeline. Epilepsy Res 2006;69: 273–294.
Ashcroft FM. From molecule to malady. Nature 2006;440: 440–447.
Peretz A, Degani N, Nachman R. Meclofenamic acid and diclofenac, novel templates of KCNQ2/Q3 potassium channel openers, depress cortical neuron activity and exhibit anticonvulsant properties. Mol Pharmacol 2005;67: 1053–1066.
Korsgaard MPG, Hartz BP, Brown WD, Ahring PK, Strøbæk D, Mirza NR. Anxiolytic effects of Maxipost (BMS-204352) and retigabine via activation of neuronal Kv7 channels. J Pharmacol Exp Ther 2005;314: 282–292.
Wei AD, Gutman GA, Aldrich R, Chandy KG, Grissmer S, Wulff H. International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels. Pharmacol Rev 2005;57: 463–472.
Ghatta S, Nimmagadda D, Xu X, O’Rourke ST. Large-conductance, calcium-activated potassium channels: structural and functional implications. Pharmacol Ther 2006; 110: 103–116.
Tricarico D, Mele A, Conte Camerino D. Carbonic anhydrase inhibitors ameliorate the symptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels. Neuromuscul Disord 2006;16: 39–45.
Tricarico D, Mele A, Conte Camerino D. Phenotype-dependent functional and pharmacological properties of BK channels in skeletal muscle: effects of microgravity. Neurobiol Dis 2005;20: 296–302.
Szewczyk A, Skalska J, Glab M, et al. Mitochondrial potassium channels: from pharmacology to function. Biochim Biophys Acta 2006;1757: 715–720.
Leniger T, Wiemann M, Bingmann D, Widman G, Hufnagel A, Bonnet U. Carbonic anhydrase inhibitor sulthiame reduces intra-cellular pH and epileptiform activity of hippocampal CA3 neurones. Epilepsia 2002;43: 469–474.
Kubo Y, Adelman JP, Clapham DE, et al. International Union of Pharmacology. LIV. Nomenclature and structure-function relationships of inwardly rectifying potassium channels. Pharmacol Rev 2005;57: 509–526.
Mannhold R. KATP channel openers: structure-activity relationships and therapeutic potentials. Med Res Rev 2004;24: 213–266.
Ligtenberg JJ, Van Haeften TW, Van Der Kolk LE, et al. Normal insulin release during sustained hyperglycaemia in hypokalaemic periodic paralysis: role of the potassium channel opener pinacidil in impaired muscle strength. Clin Sci (Lond) 1996;91: 583–589.
Wu L, Shen F, Lin L, Zhang X, Bruce IC, Xia Q. The neuroprotection conferred by activating the mitochondrial ATP-sensitive K+ channel is mediated by inhibiting the mitochondrial permeability transition pore. Neurosci Lett 2006;402: 184–189.
Tricarico D, Barbieri M, Laghezza A, Tortorella P, Loiodice F, Conte Camerino D. Dualistic actions of cromakalim and new potent 2H-1,4-benzoxazine derivatives on the native skeletal muscle KATP channel. Br J Pharmacol 2003;139: 255–262.
Tricarico D, Mele A, Lundquist AL, Desai RR, George AL Jr, Conte Camerino D. Hybrid assemblies of ATP-sensitive K+ channels determine their muscle-type-dependent biophysical and pharmacological properties. Proc Natl Acad Sci U S A 2006; 103: 1118–1123.
Lesage F. Pharmacology of neuronal background potassium channels. Neuropharmacology 2003;44: 1–7.
Catteral WA, Perez-Reyes E, Snutch TP, Striessnig J. International Union of Pharmacology. XLVIII. Nomenclature and structure-function relationships of voltage-gated calcium channels. Pharmacol Rev 2005;57: 411–425.
Spacey SD, Hildebrand ME, Materek LA, Bird TD, Snutch TP. Functional implications of a novel EA2 mutation in the P/Q-type calcium channel. Ann Neurol 2004;56: 213–220.
McNaughton NCL, Davies CH, Randall A. Inhibition of α1E Ca2+ channels by carbonic anhydrase inhibitors. J Pharmacol Sci 2004; 95: 240–247.
Cannon SC, Corey DP. Loss of Na+ channel inactivation by anemone toxin (ATX II) mimics the myotonic state in hyperkalaemic periodic paralysis. J Physiol 1993;466: 501–520.
Desaphy JF, Conte Camerino D, Franchini C, Lentini G, Tortorella V, De Luca A. Increased hindrance on the chiral carbon atom of mexiletine enhances the block of rat skeletal muscle Na+ channels in a model of myotonia induced by ATX. Br J Pharmacol 1999; 128: 1165–1174.
Clare JJ, Tate SN, Nobbs M, Romanos MA. Voltage-gated sodium channels as therapeutic targets. Drug Discov Today 2000;5: 506–520.
Glaaser IW, Clancy CE. Cardiac Na+ channels as therapeutic targets for antiarrhythmic agents. Handb Exp Pharmacol 2006;171: 99–121.
Yarov-Yarovoy V, McPhee JC, Idsvoog D, Pate C, Scheuer T, Catterall WA. Role of amino acid residues in transmembrane segments IS6 and IIS6 of the Na+ channel α subunit in voltage-dependent gating and drug block. J Biol Chem 2002;277: 35393–35401.
Hille B. Ion channels of excitable membranes. 3rd ed. Sunderland, MA: Sinauer Associates; 2001.
Heatwole C, Moxley RT III. The nondystrophic myotonias. Neurotherapeutics 2007;4: 238–251.
Trip J, Drost G, van Engelen BG, Faber CG. Drug treatment for myotonia. Cochrane Database Syst Rev 2006;1: CD004762.
Weckbecker K, Wurz A, Mohammadi B, et al. Different effects of mexiletine on two mutant sodium channels causing paramyotonia congenita and hyperkalemic periodic paralysis. Neuromuscul Disord 2000;10: 31–39.
Desaphy J-F, De Luca A, Tortorella P, De Vito D, George AL Jr, Conte Camerino D. Gating of myotonic Na channel mutants defines the response to mexiletine and a potent derivative. Neurology 2001;57: 1849–1857.
Takahashi MP, Cannon SC. Mexiletine block of disease-associated mutations in S6 segments of the human skeletal muscle Na+ channel. J Physiol 2001;537: 701–714.
Desaphy J-F, De Luca A, Didonna MP, George AL Jr, Conte Camerino D. Different flecainide sensitivity of hNav1.4 channels and myotonic mutants explained by state-dependent block. J Physiol 2004;554: 321–334.
Berkovic SF. Influence of molecular genetic advances on therapy for the idiopathic epilepsies. Neurotherapeutics 2007 (in press).
Heron SE, Scheffer IE, Berkovic SF, et al. Channelopathies in idiopathic epilepsy. Neurotherapeutics 2007;4: 295–304.
Lucas PT, Meadows LS, Nicholls J, Ragsdale DS. An epilepsy mutation in the β1 subunit of the voltage-gated sodium channel results in reduced channel sensitivity to phenytoin. Epilepsy Res 2005;64: 77–84.
Tate SK, Depondt C, Sisodiya SM, et al. Genetic predictors of the maximum doses patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Proc Natl Acad Sci U S A 2005;102: 5507–5512.
Legroux-Crespel E, Sassolas B, Guillet G, Kupfer I, Dupre D, Misery L. Treatment of familial erythermalgia with the association of lidocaine and mexiletine [In French]. Ann Dermatol Venereol 2003;130: 429–433.
Waxman SG, Dib-Hajj S. Erythermalgia: molecular basis for an inherited pain syndrome. Trends Mol Med 2005;11: 555–562.
Waxman SG, Hains BC. Fire and phantoms after spinal cord injury: Na+ channels and central pain. Trends Neurosci 2006;29: 207–215.
Lai J, Porreca F, Hunter JC, Gold MS. Voltage-gated sodium channels and hyperalgesia. Annu Rev Pharmacol Toxicol 2004;44: 371–397.
Nassar MA, Baker MD, Levato A, et al. Nerve injury induces robust allodynia and ectopic discharges in Nav1.3 null mutant mice. Mol Pain 2006;2: 33.
Sindrup SH, Jensen TS. Are sodium channel blockers useless in peripheral neuropathic pain? [Editorial]. Pain 2006 Oct. 17 [Epub ahead of print].
Wang GK, Russell C, Wang SY. State-dependent block of voltage-gated Na+ channels by amitriptyline via the local anesthetic receptor and its implication for neuropathic pain. Pain 2004;110: 166–174.
Meola G, Sansone V. Treatment in myotonia and periodic paralysis. Rev Neurol (Paris) 2004;160: S55-S69.
Hemmings HC Jr. Neuroprotection by Na+ channel blockade. J Neurosurg Anesthesiol 2004;16: 100–101.
Lenkey N, Karoly R, Kiss JP, Szasz BK, Vizi ES, Mike A. The mechanism of activity-dependent sodium channel inhibition by the antidepressants fluoxetine and desipramine. Mol Pharmacol 2006; 70: 2052–2063.
Wallace CH, Baczko I, Jones L, Fercho M, Light PE. Inhibition of cardiac voltage-gated sodium channels by grape polyphenols. Br J Pharmacol 2006;149: 657–665.
Desaphy JF, Piemo S, De Luca A, Didonna P, Conte Camerino D. Different ability of clenbuterol and salbutamol to block sodium channels predicts their therapeutic use in muscle excitability disorders. Mol Pharmacol 2003;63: 659–670.
Bezzina CR, Tan HL. Pharmacological rescue of mutant ion channels. Cardiovasc Res 2002;55: 229–232.
Jentsch TJ, Poet M, Fuhrmann JC, Zdebik AA. Physiological functions of CLC Cl− channels gleaned from human genetic disease and mouse models. Annu Rev Physiol 2005;67: 779–807.
Pusch M, Liantonio A, De Luca A, Conte Camerino D. Pharmacology of CLC chloride channels and transporters. In: Pusch M, editor. Chloride movements across cellular membranes. Advances in Molecular and Cell Biology 38. Amsterdam: Elsevier; 2007: 83–107.
Cuppoletti J, Malinowska DH, Tewari KP, et al. SPI-0211 activates T84 cell chloride transport and recombinant human C1C-2 chloride currents. Am J Physiol Cell Physiol 2004;287: C1173-C1183.
De Luca A, Piemo S, Liantonio A, Camerino C, Conte Camerino D. Phosphorylation and IGF-1-mediated dephosphorylation pathways control the activity and the pharmacological properties of skeletal muscle chloride channels. Br J Pharmacol 1998; 125: 477–482.
Conte Camerino D, Tricarico D, Piemo S, et al. Taurine and skeletal muscle disorders. Neurochem Res 2004;29: 135–142.
Eguchi H, Tsujino A, Kaibara M, et al. Acetazolamide acts directly on the human skeletal muscle chloride channel. Muscle Nerve 2006;34: 292–297.
Desaphy J-F, Rolland J-F, Valente EM, LoMonaco M, Conte Camerino D. Functional alteration of C1C-1 channel mutants associated with transient weakness in myotonia congenita [Abstract 1291-Pos]. Biophys J 2007 [Epub in advance of print].
Bowery NG, Smart TG. GABA and glycine as neurotransmitters: a brief history. Br J Pharmacol 2006;147: S109-S119.
Cascio M. Modulating inhibitory ligand-gated ion channels. AAPS J 2006;8: E353-E361.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Camerino, D.C., Tricarico, D. & Desaphy, JF. Ion channel pharmacology. Neurotherapeutics 4, 184–198 (2007). https://doi.org/10.1016/j.nurt.2007.01.013
Issue Date:
DOI: https://doi.org/10.1016/j.nurt.2007.01.013