New molecular targets for antiepileptic drugs: alpha(2)delta, SV2A, and K(v)7/KCNQ/M potassium channels.

Many currently prescribed antiepileptic drugs (AEDs) act via voltage-gated sodium channels, through effects on gamma-aminobutyric acid-mediated inhibition, or via voltage-gated calcium channels. Some newer AEDs do not act via these traditional mechanisms. The molecular targets for several of these nontraditional AEDs have been defined using cellular electrophysiology and molecular approaches. Here, we describe three of these targets: alpha(2)delta, auxiliary subunits of voltage-gated calcium channels through which the gabapentinoids gabapentin and pregabalin exert their anticonvulsant and analgesic actions; SV2A, a ubiquitous synaptic vesicle glycoprotein that may prepare vesicles for fusion and serves as the target for levetiracetam and its analog brivaracetam (which is currently in late-stage clinical development); and K(v)7/KCNQ/M potassium channels that mediate the M-current, which acts a brake on repetitive firing and burst generation and serves as the target for the investigational AEDs retigabine and ICA-105665. Functionally, all of the new targets modulate neurotransmitter output at synapses, focusing attention on presynaptic terminals as critical sites of action for AEDs.

[1]  H. Lerche,et al.  Nervous system KV7 disorders: breakdown of a subthreshold brake , 2008, The Journal of physiology.

[2]  W. A. Wilson,et al.  N-(6-Chloro-pyridin-3-yl)-3,4-difluoro-benzamide (ICA-27243): A Novel, Selective KCNQ2/Q3 Potassium Channel Activator , 2008, Molecular Pharmacology.

[3]  S. N. Mandhane,et al.  Timed pentylenetetrazol infusion test: A comparative analysis with s.c.PTZ and MES models of anticonvulsant screening in mice , 2007, Seizure.

[4]  J. Salzer,et al.  Nodes of Ranvier and axon initial segments are ankyrin G–dependent domains that assemble by distinct mechanisms , 2007, The Journal of cell biology.

[5]  Annette C. Dolphin,et al.  Functional biology of the α 2 δ subunits of voltage-gated calcium channels , 2007 .

[6]  W. Alves,et al.  Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures , 2007, Neurology.

[7]  Hua Hu,et al.  M-Channels (Kv7/KCNQ Channels) That Regulate Synaptic Integration, Excitability, and Spike Pattern of CA1 Pyramidal Cells Are Located in the Perisomatic Region , 2007, The Journal of Neuroscience.

[8]  H. Parnas,et al.  The chemical synapse goes electric: Ca2+- and voltage-sensitive GPCRs control neurotransmitter release , 2007, Trends in Neurosciences.

[9]  S. Donevan,et al.  Ca2+ channel α2δ ligands: novel modulators of neurotransmission , 2007 .

[10]  Frances K. Skinner,et al.  Somatodendritic Kv7/KCNQ/M Channels Control Interspike Interval in Hippocampal Interneurons , 2006, The Journal of Neuroscience.

[11]  J. Storm,et al.  Kv7/KCNQ/M‐channels in rat glutamatergic hippocampal axons and their role in regulation of excitability and transmitter release , 2006, The Journal of physiology.

[12]  Vann Bennett,et al.  A Common Ankyrin-G-Based Mechanism Retains KCNQ and NaV Channels at Electrically Active Domains of the Axon , 2006, The Journal of Neuroscience.

[13]  Kristina D. Micheva,et al.  Pregabalin Reduces the Release of Synaptic Vesicles from Cultured Hippocampal Neurons , 2006, Molecular Pharmacology.

[14]  Michael A. Rogawski,et al.  Diverse mechanisms of antiepileptic drugs in the development pipeline , 2006, Epilepsy Research.

[15]  C. Sommer,et al.  Immunohistochemical analysis of KCNQ3 potassium channels in mouse brain , 2006, Neuroscience Letters.

[16]  R. Kaji,et al.  KCNQ channels mediate IKs, a slow K+ current regulating excitability in the rat node of Ranvier , 2006, The Journal of physiology.

[17]  A. Randall,et al.  KCNQ/Kv7 channel regulation of hippocampal gamma-frequency firing in the absence of synaptic transmission. , 2006, Journal of neurophysiology.

[18]  S. Olesen,et al.  K(v)7 channels: function, pharmacology and channel modulators. , 2006, Current topics in medicinal chemistry.

[19]  Eric A. Johnson,et al.  SV2 Is the Protein Receptor for Botulinum Neurotoxin A , 2006, Science.

[20]  C. Sommer,et al.  Immunohistochemical analysis of KCNQ2 potassium channels in adult and developing mouse brain , 2006, Brain Research.

[21]  Y. Yaari,et al.  Axo-somatic and apical dendritic Kv7/M channels differentially regulate the intrinsic excitability of adult rat CA1 pyramidal cells. , 2006, Journal of neurophysiology.

[22]  W. Frankel,et al.  A Spontaneous Mutation Involving Kcnq2 (Kv7.2) Reduces M-Current Density and Spike Frequency Adaptation in Mouse CA1 Neurons , 2006, The Journal of Neuroscience.

[23]  M. Rogawski.  Molecular targets versus models for new antiepileptic drug discovery , 2006, Epilepsy Research.

[24]  N. S. Austin,et al.  Synaptic Vesicle Protein 2 Enhances Release Probability at Quiescent Synapses , 2006, The Journal of Neuroscience.

[25]  Heike Wulff,et al.  International Union of Pharmacology. LIII. Nomenclature and Molecular Relationships of Voltage-Gated Potassium Channels , 2005, Pharmacological Reviews.

[26]  P. Delmas,et al.  Pathways modulating neural KCNQ/M (Kv7) potassium channels , 2005, Nature Reviews Neuroscience.

[27]  T. Friedrich,et al.  Molecular Determinants of KCNQ (Kv7) K+ Channel Sensitivity to the Anticonvulsant Retigabine , 2005, The Journal of Neuroscience.

[28]  W. Frankel,et al.  Mice Carrying the Szt1 Mutation Exhibit Increased Seizure Susceptibility and Altered Sensitivity to Compounds Acting at the M‐Channel , 2004, Epilepsia.

[29]  M. Cunningham,et al.  Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro , 2004, The European journal of neuroscience.

[30]  J. Minna,et al.  Cerebellar ataxia, seizures, premature death, and cardiac abnormalities in mice with targeted disruption of the Cacna2d2 gene. , 2004, The American journal of pathology.

[31]  Y. Yaari,et al.  KCNQ/M Channels Control Spike Afterdepolarization and Burst Generation in Hippocampal Neurons , 2004, The Journal of Neuroscience.

[32]  N. Klugbauer,et al.  entla, a Novel Epileptic and Ataxic Cacna2d2 Mutant of the Mouse* , 2004, Journal of Biological Chemistry.

[33]  S. Scherer,et al.  KCNQ2 Is a Nodal K+ Channel , 2004, The Journal of Neuroscience.

[34]  M. Gillard,et al.  Discovery of 4-substituted pyrrolidone butanamides as new agents with significant antiepileptic activity. , 2004, Journal of medicinal chemistry.

[35]  Maurizio Taglialatela,et al.  M Channels Containing KCNQ2 Subunits Modulate Norepinephrine, Aspartate, and GABA Release from Hippocampal Nerve Terminals , 2004, The Journal of Neuroscience.

[36]  B. Lynch,et al.  Localization and photoaffinity labelling of the levetiracetam binding site in rat brain and certain cell lines. , 2003, European journal of pharmacology.

[37]  D. A. Brown,et al.  Effect of the KCNQ potassium channel opener retigabine on single KCNQ2/3 channels expressed in CHO cells , 2003, The Journal of physiology.

[38]  K. Mackie,et al.  Antibodies and a cysteine‐modifying reagent show correspondence of M current in neurons to KCNQ2 and KCNQ3 K+ channels , 2002, British journal of pharmacology.

[39]  D. A. Brown,et al.  Molecular correlates of the M‐current in cultured rat hippocampal neurons , 2002, The Journal of physiology.

[40]  J. J. Dougherty,et al.  Gabapentin inhibits presynaptic Ca(2+) influx and synaptic transmission in rat hippocampus and neocortex. , 2002, European journal of pharmacology.

[41]  K. Wilcox,et al.  Effects of the anticonvulsant retigabine on cultured cortical neurons: changes in electroresponsive properties and synaptic transmission. , 2002, Molecular pharmacology.

[42]  H. Clusmann,et al.  Inhibition of neuronal Ca2+ influx by gabapentin and pregabalin in the human neocortex , 2002, Neuropharmacology.

[43]  E. Lander,et al.  Ducky Mouse Phenotype of Epilepsy and Ataxia Is Associated with Mutations in the Cacna2d2 Gene and Decreased Calcium Channel Current in Cerebellar Purkinje Cells , 2001, The Journal of Neuroscience.

[44]  D. A. Brown,et al.  Activation of Expressed KCNQ Potassium Currents and Native Neuronal M-Type Potassium Currents by the Anti-Convulsant Drug Retigabine , 2001, The Journal of Neuroscience.

[45]  N. Klugbauer,et al.  Calcium Channel α2δ Subunits—Structure and Gabapentin Binding , 2001 .

[46]  J Robbins,et al.  KCNQ potassium channels: physiology, pathophysiology, and pharmacology. , 2001, Pharmacology & therapeutics.

[47]  T. Jegla,et al.  Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels. , 2000, Molecular pharmacology.

[48]  M. Rogawski.  KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications for therapy , 2000, Trends in Neurosciences.

[49]  Thomas J. Jentsch,et al.  KCNQ5, a Novel Potassium Channel Broadly Expressed in Brain, Mediates M-type Currents* , 2000, The Journal of Biological Chemistry.

[50]  S. Burbidge,et al.  Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. , 2000, Molecular pharmacology.

[51]  A. Wei,et al.  Molecular Cloning and Functional Expression of KCNQ5, a Potassium Channel Subunit That May Contribute to Neuronal M-current Diversity* , 2000, The Journal of Biological Chemistry.

[52]  Kortaro Tanaka,et al.  Disruption of the Epilepsy KCNQ2 Gene Results in Neural Hyperexcitability , 2000, Journal of neurochemistry.

[53]  W. Löscher,et al.  Anticonvulsant efficacy of gabapentin and levetiracetam in phenytoin-resistant kindled rats , 2000, Epilepsy Research.

[54]  M. Berger,et al.  Colocalization and coassembly of two human brain M-type potassium channel subunits that are mutated in epilepsy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[55]  R. Netzer,et al.  The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits , 2000, Neuroscience Letters.

[56]  S. Borosky,et al.  Inhibition of K+-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin , 2000, Neuroscience Letters.

[57]  Brian D. Hale,et al.  Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A). , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Christian Rosenmund,et al.  SV2 SVeeping Up Excess Ca2+ or TranSVorming Presynaptic Ca2+ Sensors? , 1999, Neuron.

[59]  Minghan Wang,et al.  Structural requirement of the calcium-channel subunit α2δ for gabapentin binding , 1999 .

[60]  J. Bryans,et al.  3‐Substituted GABA analogs with central nervous system activity: A review , 1999, Medicinal research reviews.

[61]  B S Brown,et al.  KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. , 1998, Science.

[62]  P. BrownJason,et al.  Cloning and Deletion Mutagenesis of the α2δ Calcium Channel Subunit from Porcine Cerebral Cortex EXPRESSION OF A SOLUBLE FORM OF THE PROTEIN THAT RETAINS [3H]GABAPENTIN BINDING ACTIVITY , 1998 .

[63]  J. Bryans,et al.  Identification of Novel Ligands for the Gabapentin Binding Site on the α2δ Subunit of a Calcium Channel and Their Evaluation as Anticonvulsant Agents , 1998 .

[64]  C. Rundfeldt.  The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells. , 1997, European journal of pharmacology.

[65]  N. O. Dalby,et al.  Comparison of the preclinical anticonvulsant profiles of tiagabine, lamotrigine, gabapentin and vigabatrin , 1997, Epilepsy Research.

[66]  D. Johnston,et al.  Axonal Action-Potential Initiation and Na+ Channel Densities in the Soma and Axon Initial Segment of Subicular Pyramidal Neurons , 1996, The Journal of Neuroscience.

[67]  J. Offord,et al.  The Novel Anticonvulsant Drug, Gabapentin (Neurontin), Binds to the Subunit of a Calcium Channel (*) , 1996, The Journal of Biological Chemistry.

[68]  J. Hénichart,et al.  The novel antiepileptic drug levetiracetam (ucb L059) appears to act via a specific binding site in CNS membranes. , 1995, European journal of pharmacology.

[69]  B. S. Brown,et al.  Reduction of spike frequency adaptation and blockade of M‐current in rat CA1 pyramidal neurones by linopirdine (DuP 996), a neurotransmitter release enhancer , 1995, British journal of pharmacology.

[70]  M. Linial,et al.  Brain contains two forms of synaptic vesicle protein 2. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[71]  G. Woodruff,et al.  Characterisation of [3H]gabapentin binding to a novel site in rat brain: homogenate binding studies. , 1993, European journal of pharmacology.

[72]  T. Vickroy.  Presynaptic cholinergic actions by the putative cognitive enhancing agent DuP 996. , 1993, The Journal of pharmacology and experimental therapeutics.

[73]  M A Rogawski,et al.  Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. , 1990, Pharmacological reviews.

[74]  D. A. Brown,et al.  Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone , 1980, Nature.

[75]  Y. Yaari,et al.  Pre- and postsynaptic activation of M-channels by a novel opener dampens neuronal firing and transmitter release. , 2007, Journal of neurophysiology.

[76]  A. Dolphin,et al.  Identification of the (cid:1) 2 - (cid:2) -1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin , 2006 .

[77]  G. Plosker,et al.  Retigabine , 2006, CNS drugs.

[78]  G. Seebohm,et al.  RETIGABINE :B ENDING POTASSIUM CHANNELS TO OUR WILL The New Anticonvulsant Retigabine Favors Voltage-dependent Opening of the Kv7.2 (KCNQ2) Channel by Binding to Its Activation Gate , 2005 .

[79]  Johan F. Storm,et al.  Kv 7 / KCNQ / M and HCN / h , but not KCa 2 / SK channels , contribute to the somatic medium after-hyperpolarization and excitability control in CA 1 hippocampal pyramidal cells , 2005 .