Last update 01 Nov 2024

Nav1.2 x Cav2.2

Last update 01 Nov 2024

Basic Info

Related Targets

Nav1.2Cav2.2

Drugs associated with Nav1.2 x Cav2.2

Sipatrigine

Target

Cav2.2 x Nav1.2

Mechanism

Cav2.2 blockers [+1]

Active Org.-

Originator Org.

GSK Plc

Active Indication-

Inactive Indication

Brain Ischemia

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with Nav1.2 x Cav2.2

100 Translational Medicine associated with Nav1.2 x Cav2.2

0 Patents (Medical) associated with Nav1.2 x Cav2.2

Literatures (Medical) associated with Nav1.2 x Cav2.2

01 Nov 2012·Journal of Comparative NeurologyQ3 · MEDICINE

Coexpression of high‐voltage‐activated ion channels Kv3.4 and Cav1.2 in pioneer axons during pathfinding in the developing rat forebrain

Q3 · MEDICINE

Article

Author: Chia Yi Huang ; Dachen Chu ; Wei Chao Hwang ; Meei Ling Tsaur

AbstractPrecise axon pathfinding is crucial for establishment of the initial neuronal network during development. Pioneer axons navigate without the help of preexisting axons and pave the way for follower axons that project later. Voltage‐gated ion channels make up the intrinsic electrical activity of pioneer axons and regulate axon pathfinding. To elucidate which channel molecules are present in pioneer axons, immunohistochemical analysis was performed to examine 14 voltage‐gated ion channels (Kv1.1–Kv1.3, Kv3.1–Kv3.4, Kv4.3, Cav1.2, Cav1.3, Cav2.2, Nav1.2, Nav1.6, and Nav1.9) in nine axonal tracts in the developing rat forebrain, including the optic nerve, corpus callosum, corticofugal fibers, thalamocortical axons, lateral olfactory tract, hippocamposeptal projection, anterior commissure, hippocampal commissure, and medial longitudinal fasciculus. We found A‐type K+ channel Kv3.4 in both pioneer axons and early follower axons and L‐type Ca2+ channel Cav1.2 in pioneer axons and early and late follower axons. Spatially, Kv3.4 and Cav1.2 were colocalized with markers of pioneer neurons and pioneer axons, such as deleted in colorectal cancer (DCC), in most fiber tracts examined. Temporally, Kv3.4 and Cav1.2 were expressed abundantly in most fiber tracts during axon pathfinding but were downregulated beginning in synaptogenesis. By contrast, delayed rectifier Kv channels (e.g., Kv1.1) and Nav channels (e.g., Nav1.2) were absent from these fiber tracts (except for the corpus callosum) during pathfinding of pioneer axons. These data suggest that Kv3.4 and Cav1.2, two high‐voltage‐activated ion channels, may act together to control Ca2+‐dependent electrical activity of pioneer axons and play important roles during axon pathfinding. J. Comp. Neurol. 520:3650–3672, 2012. © 2012 Wiley Periodicals, Inc.

Frontiers in Molecular NeuroscienceQ2 · MEDICINE

Proestrus Differentially Regulates Expression of Ion Channel and Calcium Homeostasis Genes in GnRH Neurons of Mice

Q2 · MEDICINE

ArticleOA

Author: Farkas, Imre ; Solymosi, Norbert ; Liposits, Zsolt ; Vastagh, Csaba

In proestrus, the changing gonadal hormone milieu alters the physiological properties of GnRH neurons and contributes to the development of the GnRH surge. We hypothesized that proestrus also influences the expression of different ion channel genes in mouse GnRH neurons. Therefore, we performed gene expression profiling of GnRH neurons collected from intact, proestrous and metestrous GnRH-GFP transgenic mice, respectively. Proestrus changed the expression of 37 ion channel and 8 calcium homeostasis-regulating genes. Voltage-gated sodium channels responded with upregulation of three alpha subunits (Scn2a1, Scn3a, and Scn9a). Within the voltage-gated potassium channel class, Kcna1, Kcnd3, Kcnh3, and Kcnq2 were upregulated, while others (Kcna4, Kcnc3, Kcnd2, and Kcng1) underwent downregulation. Proestrus also had impact on inwardly rectifying potassium channel subunits manifested in enhanced expression of Kcnj9 and Kcnj10 genes, whereas Kcnj1, Kcnj11, and Kcnj12 subunit genes were downregulated. The two-pore domain potassium channels also showed differential expression with upregulation of Kcnk1 and reduced expression of three subunit genes (Kcnk7, Kcnk12, and Kcnk16). Changes in expression of chloride channels involved both the voltage-gated (Clcn3 and Clcn6) and the intracellular (Clic1) subtypes. Regarding the pore-forming alpha-1 subunits of voltage-gated calcium channels, two (Cacna1b and Cacna1h) were upregulated, while Cacna1g showed downregulation. The ancillary subunits were also differentially regulated (Cacna2d1, Cacna2d2, Cacnb1, Cacnb3, Cacnb4, Cacng5, Cacng6, and Cacng8). In addition, ryanodine receptor 1 (Ryr1) gene was downregulated, while a transient receptor potential cation channel (Trpm3) gene showed enhanced expression. Genes encoding proteins regulating the intracellular calcium homeostasis were also influenced (Calb1, Hpca, Hpcal1, Hpcal4, Cabp7, Cab 39l, and Cib2). The differential expression of genes coding for ion channel proteins in GnRH neurons at late proestrus indicates that the altering hormone milieu contributes to remodeling of different kinds of ion channels of GnRH neurons, which might be a prerequisite of enhanced cellular activity of GnRH neurons and the subsequent surge release of the neurohormone.

Fine-mapping genomic loci refines bipolar disorder risk genes

Article

Author: Won, Hong-Hee ; Cairns, Murray J. ; Jonsson, Lina ; Green, Melissa J ; Lissowska, Jolanta ; Owen, Michael J. ; O 'Connell, Kevin S ; Coombes, Brandon ; Ophoff, Roel A. ; Myers, Richard M ; Jones, Ian ; Gizer, Ian R ; Bengesser, Susanne ; Chatzinakos, Chris ; Mayoral, Fermin ; Adams, Mark ; Witt, Stephanie H. ; Leboyer, Marion ; Forstner, Andreas J ; Nenadić, Igor ; Tooney, Paul ; Świątkowska, Beata ; Kelsoe, John R ; Martin, Nicholas G. ; Ramos-Quiroga, Josep Antoni ; Braun, Alice ; Pawlak, Joanna M. ; Andlauer, Till F M ; Waldman, Irwin D. ; Vincent, John B. ; Nurnberger, John ; Weickert, Cynthia Shannon ; Guzman-Parra, José ; Ophoff, Roel A ; Green, Melissa J. ; Craddock, Nicholas ; Weickert, Thomas ; Smoller, Jordan W. ; Moutsatsou, Paraskevi ; Waldman, Irwin D ; Patrinos, George P. ; Gawlik, Micha ; Forstner, Andreas J. ; Carr, Vaughan J. ; Kirov, George ; Shannon Weickert, Cynthia ; Kittel-Schneider, Sarah ; Mathews, Carol A ; Nievergelt, Caroline ; Pato, Michele T. ; Hahn, Tim ; Andreassen, Ole A ; Myers, Richard M. ; Mathews, Carol A. ; Ribasés, Marta ; Fellendorf, Frederike Tabea ; Corvin, Aiden ; Koromina, Maria ; Nöthen, Markus M. ; Panagiotaropoulou, Georgia ; Hong, Kyung Sue ; Scott, Rodney J. ; Dikeos, Dimitris ; Schilder, Brian M. ; Porichi, Evgenia ; Jablensky, Assen V. ; Fullerton, Janice M ; Dafnas, Konstantinos ; Forty, Liz ; Landén, Mikael ; Schofield, Peter R ; Martin, Nicholas G ; Antoniou, Anastasia ; Toma, Claudio ; Cichon, Sven ; Grigoroiu-Serbanescu, Maria ; Pato, Carlos ; Kelsoe, John R. ; Maratou, Eirini ; McGregor, Nathaniel W ; Ferentinos, Panagiotis ; McElroy, Susan L. ; Frye, Mark ; Schofield, Peter R. ; Reif, Andreas ; Adolfsson, Rolf ; Liu, Xiaoxi ; Lenger, Melanie ; Mullins, Niamh ; O’Donovan, Claire ; Di Florio, Arianna ; Baune, Bernhard T ; Jablensky, Assen V ; Florio, Arianna Di ; Müller-Myhsok, Bertram ; Jones, Lisa ; Stein, Dan J. ; O'Donovan, Claire ; Schulze, Thomas G. ; Fullerton, Janice M. ; Reininghaus, Eva Z. ; Ikeda, Masashi ; Schall, Ulrich ; O.’Donovan, Michael ; Edenberg, Howard J. ; Alda, Martin ; Iwata, Nakao ; Gizer, Ian R. ; Andreassen, Ole A. ; Biernacka, Joanna ; Schulze, Thomas G ; Ripke, Stephan ; Bidgeli, Tim ; Alfredsson, Lars ; Vieta, Eduard ; Bosch, Rosa ; McQuillin, Andrew ; Baune, Bernhard T. ; Vincent, John B ; Humphrey, Jack ; Coleman, Jonathan R I ; Ravi, Ashvin ; Kogevinas, Manolis ; Henskens, Frans ; Kim, Jaeyoung ; Dannlowski, Udo ; Loughland, Carmel ; Streit, Fabian ; Boehnke, Michael ; Kircher, Tilo ; Smoller, Jordan W ; Perlis, Roy H. ; Michie, Patricia ; Rietschel, Marcella ; Edenberg, Howard J ; Lochner, Christine ; Artigas, Maria Soler ; McGregor, Nathaniel W. ; MacIntyre, Donald ; Schilder, Brian M ; Vawter, Marquis P. ; Perlis, Roy H ; Scott, Laura ; Reininghaus, Eva Z ; Witt, Stephanie H ; Stein, Dan J ; Pantelis, Christos ; Soler Artigas, Maria ; Gordon-Smith, Katherine ; Andlauer, Till F. M. ; Pato, Michele T ; Degenhardt, Franziska ; Vawter, Marquis P ; Coleman, Jonathan R. I. ; Serretti, Alessandro ; Scott, Rodney J ; Raj, Towfique ; McElroy, Susan L ; Nöthen, Markus M ; Rolf, Adolfsson ; Mowry, Bryan ; Hillert, Jan ; Dalkner, Nina ; Patrinos, George P ; Mitchell, Philip B. ; O 'Donovan, Michael ; O.’Connell, Kevin S. ; Terao, Chikashi ; McIntosh, Andrew ; Posthuma, Danielle ; Pawlak, Joanna M ; Owen, Michael J ; Mitchell, Philip B ; Casas, Miquel ; Carr, Vaughan J ; Catts, Stanley ; Cairns, Murray J

AbstractBipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 17 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of genes involved in neurotransmission and neurodevelopment includingSCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, CRTC3, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, DPH1, GSDMB, MED24andTHRAin BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance of BD polygenic risk scores across diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

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