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Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Ion Channel Pharmacology Diana Conte Camerino, Domenico Tricarico, and Jean-François Desaphy Pharmacology Division, Department of Pharmacobiology, School of Pharmacy, University of Bari, Bari, Italy Summary: Because ion channels are involved in many cellular tions have demonstrated that channel mutations can either in- processes, drugs acting on ion channels have long been used for crease or decrease affinity for the drug, modifying its potential the treatment of many diseases, especially those affecting elec- therapeutic effect. Together with the discovery of channel gene trically excitable tissues. The present review discusses the phar- polymorphisms that may affect drug pharmacodynamics, these macology of voltage-gated and neurotransmitter-gated ion findings highlight the need for pharmacogenetic research to channels involved in neurologic diseases, with emphasis on allow identification of drugs with more specific effects on neurologic channelopathies. With the discovery of ion chan- channel isoforms or mutants, to increase efficacy and reduce nelopathies, the therapeutic value of many basic drugs targeting side effects. With a greater understanding of channel genetics, ion channels has been confirmed. The understanding of the structure, and function, together with the identification of novel genotype–phenotype relationship has highlighted possible ac- primary and secondary channelopathies, the number of ion tion mechanisms of other empirically used drugs. Moreover, channel drugs for neurologic channelopathies will increase sub- other ion channels have been pinpointed as potential new Key Words: drug targets. With regards to therapy of channelopathies, ex- stantially. Voltage-gated, neurotransmitter-gated, perimental investigations of the intimate drug–channel interac- ion channel, drug therapy, channelopathy, pharmacogenetics. INTRODUCTION channels.1 Beyond their usefulness in the clinical setting, natural ion channel ligands, especially toxins with high Ion channels are involved in many, if not all, cellular functions and are altered in many pathological conditions binding affinity, have also largely contributed to the dis- either indirectly or directly, as in the channelopathies. It covery of the various ion channels and the understanding is not surprising, therefore, that drugs targeting ion chan- of their structure and function long before their molecu- nels constitute important therapeutic interventions for a lar identification. number of diseases. The use of ion channel modulators Historically, the role of ion channels was most obvious as drugs was operative long before their existence be- in the membrane of electrically excitable cells, such as came known. Ion channel function is modulated by many the neuron, the cardiac myocyte, and the skeletal muscle natural agents of the animal and plant kingdoms, which fiber. Consequently, a number of drugs able to modulate contribute to the dangerous effects of poisons or the cell excitability by acting on voltage-gated or neurotrans- beneficial effects of medicinal herbs. Once isolated, mitter-gated ion channels in these tissues have reached these lead compounds have served as the basis for the blockbuster status in the pharmaceutical industry, gener- synthesis of more specific ligands with fewer side ef- ating large profits. Examples are the antiepileptic drugs fects. For instance, cocaine extracted from coca leaves (AEDs), which include blockers of voltage-gated sodium entered clinical practice in the 1880s for its analgesic and calcium channels, agonists of GABAA receptors, properties, but the occurrence of CNS and cardiovascular and, more recently, openers of potassium channels and toxicity led medicinal chemists to synthesize new deriv- antagonists of AMPA and NMDA glutamate receptors. atives, thus giving rise to the pharmaceutical class of Today more than 400 genes are known that encode local anesthetics, which are selective blockers of sodium even more ion channel subunits due to alternative splic- ing, each subunit being likely the target of many phar- macological agents. Covering all drugs acting on ion Address correspondence and reprint requests to: Diana Conte Cam- channels is beyond the scope of this review, which will erino, Ph.D., Sezione di Farmacologia, Dipartimento FarmacoBio- logico, Facoltà di Farmacia, Università degli Studi di Bari, via Orabona instead focus mainly on drugs acting on ion channels 4 – CAMPUS, I-70125, Bari, Italy. E-mail: [email protected]. involved in neurologic disorders and especially their use 184 Vol. 4, 184–198, April 2007 © The American Society for Experimental NeuroTherapeutics, Inc. ION CHANNEL PHARMACOLOGY 185 in channelopathies. The sections that follow each detail channels participate to the repolarization of the postsyn- the pharmacology of an ion channel family. In addition, aptic action potential.2,3 Kv3.1Ϫ/Ϫ mice show impaired a synopsis of drug information for the neurologic chan- motor skills and reduced muscle contraction force. Dou- nelopathies is provided in Table 1. ble Kv3.1/Kv3.3 knockout mice show ataxia, myoclo- nus, and other neurological abnormalities. Kv channels are also involved in neurological symptoms observed in PHARMACOLOGY OF POTASSIUM paraneoplastic neurological syndromes, which are re- CHANNELS mote effects of cancer with an autoimmune response 5 ϩ against CNS and peripheral nervous antigens. - K channels are classified on the basis of the primary In neuro myotonia associated with limbic encephalitis and small amino acid sequence of the pore-containing unit (␣-sub- ϩ cell lung cancer cells (SCLC), function of Kv1.1/Kv1.2 unit) into three major families: 1) voltage-gated K channels is progressively lost because of an abnormally channels (Kv) containing six or seven transmembrane enhanced turnover and degradation of the proteins. The regions with a single pore, including also KCNQ, hERG, 2ϩ ϩ immune system is also modulated by the Kv1.3 channel, eag, and the Ca -activated K channels; 2) inward which is expressed in many cells involved in immune rectifiers (Kir) containing only two transmembrane re- 5 gions and a single pore; and 3) two-pore tandem Kϩ responses and is a drug target. Kv channel blockers. ϩ channels containing four transmembrane segments with The voltage-gated K channels have been investigated through the use of peptide toxins two pores. The pore subunits coassemble with auxiliary from animals and plants, such as dendrototoxins, kali- subunits, affecting their pharmacological responses and toxin, hongotoxin, margatoxin, and others that block the modulation by second messengers. channel pore at picomolar to nanomolar concentrations Pharmacology of voltage-gated potassium and serve as tools for the analysis of their structure– (Kv) channels function relationships. These toxins block Kv1.1–6 2,6 Following the cloning of the four Kϩ channel genes in channel subtypes. Although Kv channels were the first Drosophila, several members of related voltage-gated Kϩ to be molecularly characterized, no selective blockers or channel (Kv) genes were identified in mammals and di- openers are currently available. Tetraethylammonium vided into eight gene families: KCNA (Kv1.1–8), KCNB (TEA) and 4-aminopyridine (4-AP) are classic Kv chan- (Kv2.1–2), KCNC (Kv3.1–4), KCND (Kv4.1–3), KCNF nel blockers, which can discriminate between various (Kv5.1), KCNG (Kv6.1–4), KCNS (Kv9.1–3) and channel subtypes. The Kv1.1, Kv3.1–4, and Kv7.2 chan- KCNV (Kv8.1–3). The Kv1–4 families can form homo- nels are more sensitive to TEA. Kv1.1–5, Kv1.7 and or heteromeric channels with other subunits from within Kv3.1–2 are inhibited by micromolar concentrations of their own family or with the electrically silent families 4-AP, but millimolar concentrations are needed to block (Kv5, Kv6, Kv8, and Kv9). The ␤-subunits of Kv chan- Kv1.6, 1.8, 2.2, 3.3 and Kv4.1–3. nels influence channel properties, trafficking, and drug Other members, such as Kv2.1, Kv3.4, hERG, eag1, responses.2 and KCNQ channels, are insensitive to 4-AP. Several Kv1.1–2 channels are involved in neuronal chan- 4-AP analogs have been tested against Kv channels, and nelopathies. Kv1.1 is expressed in many neurons, motor the order of potency as Kv inhibitors ranks as follows 7 neurons, retina, and heart and skeletal muscle, whereas 3,4-DAP Ͼ 4-AP Ͼ 3-AP Ͼ 2-AP. These drugs cause Kv1.2 is expressed mainly in the cerebellum, hippocam- neuronal firing and release of neurotransmitters such as pus, and thalamus. These low-voltage activated channels, acetylcholine (ACh). Thus, 4-AP and 3,4-diaminopyri- located in the axons of neurons, do not affect the first dine (3,4-DAP) (EU/3/02/124) (25–60 mg/day) are ef- action potential but increase the action potential thresh- fective in those conditions associated with loss or re- old.3 Kv1.1 and Kv1.2 can form heteromultimers impor- duced quantal release of neurotransmitters such as tant for repolarization of the presynapsis in neurons and episodic ataxias, myasthenia gravis (MG), Lambert– skeletal muscle. Eaton myasthenic syndromes (LEMS), and degenerative Loss-of-function mutations of KCNA1 are associated cognitive disorders. with episodic ataxia type 1 (EA1), which is characterized In episodic ataxias type 2 and 6 (EA2 and EA6) the by episodic failure of cerebellar excitation, while hyper- drugs enhance the excitability of spinocerebellar axis excitability of motor neurons is commonly observed. An that is compromised by gain-of-function mutations of
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