Potassium Channels: Structures, Diseases, and Modulators
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Reframing Psychiatry for Precision Medicine
Reframing Psychiatry for Precision Medicine Elizabeth B Torres 1,2,3* 1 Rutgers University Department of Psychology; [email protected] 2 Rutgers University Center for Cognitive Science (RUCCS) 3 Rutgers University Computer Science, Center for Biomedicine Imaging and Modelling (CBIM) * Correspondence: [email protected]; Tel.: (011) +858-445-8909 (E.B.T) Supplementary Material Sample Psychological criteria that sidelines sensory motor issues in autism: The ADOS-2 manual [1, 2], under the “Guidelines for Selecting a Module” section states (emphasis added): “Note that the ADOS-2 was developed for and standardized using populations of children and adults without significant sensory and motor impairments. Standardized use of any ADOS-2 module presumes that the individual can walk independently and is free of visual or hearing impairments that could potentially interfere with use of the materials or participation in specific tasks.” Sample Psychiatric criteria from the DSM-5 [3] that does not include sensory-motor issues: A. Persistent deficits in social communication and social interaction across multiple contexts, as manifested by the following, currently or by history (examples are illustrative, not exhaustive, see text): 1. Deficits in social-emotional reciprocity, ranging, for example, from abnormal social approach and failure of normal back-and-forth conversation; to reduced sharing of interests, emotions, or affect; to failure to initiate or respond to social interactions. 2. Deficits in nonverbal communicative behaviors used for social interaction, ranging, for example, from poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body language or deficits in understanding and use of gestures; to a total lack of facial expressions and nonverbal communication. -
The CB2 Receptor As a Novel Therapeutic Target for Epilepsy Treatment
International Journal of Molecular Sciences Review The CB2 Receptor as a Novel Therapeutic Target for Epilepsy Treatment Xiaoyu Ji 1, Yang Zeng 2 and Jie Wu 1,* 1 Brain Function and Disease Laboratory, Shantou University Medical College, Xin-Ling Road #22, Shantou 515041, China; [email protected] 2 Medical Education Assessment and Research Center, Shantou University Medical College, Xin-Ling Road #22, Shantou 515041, China; [email protected] * Correspondence: [email protected] or [email protected] Abstract: Epilepsy is characterized by repeated spontaneous bursts of neuronal hyperactivity and high synchronization in the central nervous system. It seriously affects the quality of life of epileptic patients, and nearly 30% of individuals are refractory to treatment of antiseizure drugs. Therefore, there is an urgent need to develop new drugs to manage and control refractory epilepsy. Cannabinoid ligands, including selective cannabinoid receptor subtype (CB1 or CB2 receptor) ligands and non- selective cannabinoid (synthetic and endogenous) ligands, may serve as novel candidates for this need. Cannabinoid appears to regulate seizure activity in the brain through the activation of CB1 and CB2 cannabinoid receptors (CB1R and CB2R). An abundant series of cannabinoid analogues have been tested in various animal models, including the rat pilocarpine model of acquired epilepsy, a pentylenetetrazol model of myoclonic seizures in mice, and a penicillin-induced model of epileptiform activity in the rats. The accumulating lines of evidence show that cannabinoid ligands exhibit significant benefits to control seizure activity in different epileptic models. In this review, we summarize the relationship between brain CB receptors and seizures and emphasize the potential 2 mechanisms of their therapeutic effects involving the influences of neurons, astrocytes, and microglia Citation: Ji, X.; Zeng, Y.; Wu, J. -
De Novo BK Channel Variant Causes Epilepsy by Affecting Voltage Gating but Not Ca2+ Sensitivity
European Journal of Human Genetics (2018) 26:220–229 https://doi.org/10.1038/s41431-017-0073-3 ARTICLE De novo BK channel variant causes epilepsy by affecting voltage gating but not Ca2+ sensitivity 1 2 3,4 5 6 Xia Li ● Sibylle Poschmann ● Qiuyun Chen ● Walid Fazeli ● Nelly Jouayed Oundjian ● 7 8 9 9,10 Francesca M. Snoeijen-Schouwenaars ● Oliver Fricke ● Erik-Jan Kamsteeg ● Marjolein Willemsen ● Qing Kenneth Wang1,3,4 Received: 18 August 2017 / Revised: 6 November 2017 / Accepted: 23 November 2017 / Published online: 12 January 2018 © European Society of Human Genetics 2018 Abstract Epilepsy is one of the most common neurological diseases and it causes profound morbidity and mortality. We identified the first de novo variant in KCNMA1 (c.2984 A > G (p.(N995S)))—encoding the BK channel—that causes epilepsy, but not paroxysmal dyskinesia, in two independent families. The c.2984 A > G (p.(N995S)) variant markedly increased the macroscopic potassium current by increasing both the channel open probability and channel open dwell time. The c.2984 A > G (p.(N995S)) variant did not affect the calcium sensitivity of the channel. We also identified three other variants of fi > > > 1234567890 unknown signi cance (c.1554 G T (p.(K518N)), c.1967A C (p.(E656A)), and c.3476 A G (p.(N1159S))) in three separate patients with divergent epileptic phenotypes. However, these variants did not affect the BK potassium current, and are therefore unlikely to be disease-causing. These results demonstrate that BK channel variants can cause epilepsy without paroxysmal dyskinesia. The underlying molecular mechanism can be increased activation of the BK channel by increased sensitivity to the voltage-dependent activation without affecting the sensitivity to the calcium-dependent activation. -
K+ Channel Modulators Product ID Product Name Description D3209 Diclofenac Sodium Salt NSAID; COX-1/2 Inhibitor, Potential K+ Channel Modulator
K+ Channel Modulators Product ID Product Name Description D3209 Diclofenac Sodium Salt NSAID; COX-1/2 inhibitor, potential K+ channel modulator. G4597 18β-Glycyrrhetinic Acid Triterpene glycoside found in Glycyrrhiza; 15-HPGDH inhibitor, hERG and KCNA3/Kv1.3 K+ channel blocker. A4440 Allicin Organosulfur found in garlic, binds DNA; inwardly rectifying K+ channel activator, L-type Ca2+ channel blocker. P6852 Propafenone Hydrochloride β-adrenergic antagonist, Kv1.4 and K2P2 K+ channel blocker. P2817 Phentolamine Hydrochloride ATP-sensitive K+ channel activator, α-adrenergic antagonist. P2818 Phentolamine Methanesulfonate ATP-sensitive K+ channel activator, α-adrenergic antagonist. T7056 Troglitazone Thiazolidinedione; PPARγ agonist, ATP-sensitive K+ channel blocker. G3556 Ginsenoside Rg3 Triterpene saponin found in species of Panax; γ2 GABA-A agonist, Kv7.1 K+ channel activator, α10 nAChR antagonist. P6958 Protopanaxatriol Triterpene sapogenin found in species of Panax; GABA-A/C antagonist, slow-activating delayed rectifier K+ channel blocker. V3355 Vindoline Semi-synthetic vinca alkaloid found in Catharanthus; Kv2.1 K+ channel blocker and H+/K+ ATPase inhibitor. A5037 Amiodarone Hydrochloride Voltage-gated Na+, Ca2+, K+ channel blocker, α/β-adrenergic antagonist, FIASMA. B8262 Bupivacaine Hydrochloride Monohydrate Amino amide; voltage-gated Na+, BK/SK, Kv1, Kv3, TASK-2 K+ channel inhibitor. C0270 Carbamazepine GABA potentiator, voltage-gated Na+ and ATP-sensitive K+ channel blocker. C9711 Cyclovirobuxine D Found in Buxus; hERG K+ channel inhibitor. D5649 Domperidone D2/3 antagonist, hERG K+ channel blocker. G4535 Glimepiride Sulfonylurea; ATP-sensitive K+ channel blocker. G4634 Glipizide Sulfonylurea; ATP-sensitive K+ channel blocker. I5034 Imiquimod Imidazoquinoline nucleoside analog; TLR-7/8 agonist, KCNA1/Kv1.1 and KCNA2/Kv1.2 K+ channel partial agonist, TREK-1/ K2P2 and TRAAK/K2P4 K+ channel blocker. -
The Mineralocorticoid Receptor Leads to Increased Expression of EGFR
www.nature.com/scientificreports OPEN The mineralocorticoid receptor leads to increased expression of EGFR and T‑type calcium channels that support HL‑1 cell hypertrophy Katharina Stroedecke1,2, Sandra Meinel1,2, Fritz Markwardt1, Udo Kloeckner1, Nicole Straetz1, Katja Quarch1, Barbara Schreier1, Michael Kopf1, Michael Gekle1 & Claudia Grossmann1* The EGF receptor (EGFR) has been extensively studied in tumor biology and recently a role in cardiovascular pathophysiology was suggested. The mineralocorticoid receptor (MR) is an important efector of the renin–angiotensin–aldosterone‑system and elicits pathophysiological efects in the cardiovascular system; however, the underlying molecular mechanisms are unclear. Our aim was to investigate the importance of EGFR for MR‑mediated cardiovascular pathophysiology because MR is known to induce EGFR expression. We identifed a SNP within the EGFR promoter that modulates MR‑induced EGFR expression. In RNA‑sequencing and qPCR experiments in heart tissue of EGFR KO and WT mice, changes in EGFR abundance led to diferential expression of cardiac ion channels, especially of the T‑type calcium channel CACNA1H. Accordingly, CACNA1H expression was increased in WT mice after in vivo MR activation by aldosterone but not in respective EGFR KO mice. Aldosterone‑ and EGF‑responsiveness of CACNA1H expression was confrmed in HL‑1 cells by Western blot and by measuring peak current density of T‑type calcium channels. Aldosterone‑induced CACNA1H protein expression could be abrogated by the EGFR inhibitor AG1478. Furthermore, inhibition of T‑type calcium channels with mibefradil or ML218 reduced diameter, volume and BNP levels in HL‑1 cells. In conclusion the MR regulates EGFR and CACNA1H expression, which has an efect on HL‑1 cell diameter, and the extent of this regulation seems to depend on the SNP‑216 (G/T) genotype. -
Table S1 the Four Gene Sets Derived from Gene Expression Profiles of Escs and Differentiated Cells
Table S1 The four gene sets derived from gene expression profiles of ESCs and differentiated cells Uniform High Uniform Low ES Up ES Down EntrezID GeneSymbol EntrezID GeneSymbol EntrezID GeneSymbol EntrezID GeneSymbol 269261 Rpl12 11354 Abpa 68239 Krt42 15132 Hbb-bh1 67891 Rpl4 11537 Cfd 26380 Esrrb 15126 Hba-x 55949 Eef1b2 11698 Ambn 73703 Dppa2 15111 Hand2 18148 Npm1 11730 Ang3 67374 Jam2 65255 Asb4 67427 Rps20 11731 Ang2 22702 Zfp42 17292 Mesp1 15481 Hspa8 11807 Apoa2 58865 Tdh 19737 Rgs5 100041686 LOC100041686 11814 Apoc3 26388 Ifi202b 225518 Prdm6 11983 Atpif1 11945 Atp4b 11614 Nr0b1 20378 Frzb 19241 Tmsb4x 12007 Azgp1 76815 Calcoco2 12767 Cxcr4 20116 Rps8 12044 Bcl2a1a 219132 D14Ertd668e 103889 Hoxb2 20103 Rps5 12047 Bcl2a1d 381411 Gm1967 17701 Msx1 14694 Gnb2l1 12049 Bcl2l10 20899 Stra8 23796 Aplnr 19941 Rpl26 12096 Bglap1 78625 1700061G19Rik 12627 Cfc1 12070 Ngfrap1 12097 Bglap2 21816 Tgm1 12622 Cer1 19989 Rpl7 12267 C3ar1 67405 Nts 21385 Tbx2 19896 Rpl10a 12279 C9 435337 EG435337 56720 Tdo2 20044 Rps14 12391 Cav3 545913 Zscan4d 16869 Lhx1 19175 Psmb6 12409 Cbr2 244448 Triml1 22253 Unc5c 22627 Ywhae 12477 Ctla4 69134 2200001I15Rik 14174 Fgf3 19951 Rpl32 12523 Cd84 66065 Hsd17b14 16542 Kdr 66152 1110020P15Rik 12524 Cd86 81879 Tcfcp2l1 15122 Hba-a1 66489 Rpl35 12640 Cga 17907 Mylpf 15414 Hoxb6 15519 Hsp90aa1 12642 Ch25h 26424 Nr5a2 210530 Leprel1 66483 Rpl36al 12655 Chi3l3 83560 Tex14 12338 Capn6 27370 Rps26 12796 Camp 17450 Morc1 20671 Sox17 66576 Uqcrh 12869 Cox8b 79455 Pdcl2 20613 Snai1 22154 Tubb5 12959 Cryba4 231821 Centa1 17897 -
Towards Mutation-Specific Precision Medicine in Atypical Clinical
International Journal of Molecular Sciences Review Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes Tadashi Nakajima * , Shuntaro Tamura, Masahiko Kurabayashi and Yoshiaki Kaneko Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi 371-8511, Gunma, Japan; [email protected] (S.T.); [email protected] (M.K.); [email protected] (Y.K.) * Correspondence: [email protected]; Tel.: +81-27-220-8145; Fax: +81-27-220-8158 Abstract: Most causal genes for inherited arrhythmia syndromes (IASs) encode cardiac ion channel- related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterol- ogous expression systems and animal models, have revealed the pathophysiology of IASs and enabled, in part, the establishment of causal gene-specific precision medicine. Additionally, the utilization of induced pluripotent stem cell (iPSC) technology have provided further insights into the patho- physiology of IASs and novel promising therapeutic strategies, especially in long QT syndrome. It is now known that there are atypical clinical phenotypes of IASs associated with specific mutations that have unique electrophysiological properties, which raises a possibility of mutation-specific precision medicine. In particular, patients with Brugada syndrome harboring an SCN5A R1632C mutation exhibit exercise-induced cardiac events, which may be caused by a marked activity-dependent loss of R1632C-Nav1.5 availability due to a marked delay of recovery from inactivation. This suggests that the use of isoproterenol should be avoided. Conversely, the efficacy of β-blocker needs to be examined. Patients harboring a KCND3 V392I mutation exhibit both cardiac (early repolarization syndrome and Citation: Nakajima, T.; Tamura, S.; paroxysmal atrial fibrillation) and cerebral (epilepsy) phenotypes, which may be associated with a Kurabayashi, M.; Kaneko, Y. -
The Action of a BK Channel Opener
COMMENTARY The action of a BK channel opener Jianmin Cui Agonists and antagonists of an ion channel are important tools to studies of ischemia and reperfusion in isolated, perfused rat probe the functional role of the channel in specific cells and hearts, Bentzen et al. found that mitochondria BK channel ac- tissues. The effects of the agonist and antagonist on the cellular tivation by NS11021 perfusion reduced tissue damage, decreas- and tissue physiology and pathophysiology can be indications ing infarct size by more than 70% (Bentzen et al., 2009; 2010). A for the ion channel as a drug target for certain diseases. Agonists similar result was observed when studies were performed in and antagonists can also be effective tools for understanding mouse hearts (Soltysinska et al., 2014; Frankenreiter et al., molecular mechanisms for function of the channel. Obviously, to 2018), and NS11021 reduced infarction area in comparison know what a tool does will help a better use of the tool. NS11021 with the BK knockout (Slo1−/−) hearts. NS11021 also increased is a BK channel opener (Bentzen et al., 2007) that has been used survival of isolated ventricular myocytes subjected to metabolic asatooltoprobethefunctionalroleofBKchannelsinvarious inhibition followed by reenergization (Borchert et al., 2013). The tissues and the molecular mechanism of BK channel gating. In cardiac protection effects of NS11021 were suggested to derive this issue of the Journal of General Physiology, Rockman et al. from a beneficial effect on energetics due to enhanced K+ uptake present a comprehensive study of NS11021 modulation of BK via BK channels that resulted in mitochondrial swelling with channels. -
Emerging Roles for Multifunctional Ion Channel Auxiliary Subunits in Cancer T ⁎ Alexander S
Cell Calcium 80 (2019) 125–140 Contents lists available at ScienceDirect Cell Calcium journal homepage: www.elsevier.com/locate/ceca Emerging roles for multifunctional ion channel auxiliary subunits in cancer T ⁎ Alexander S. Hawortha,b, William J. Brackenburya,b, a Department of Biology, University of York, Heslington, York, YO10 5DD, UK b York Biomedical Research Institute, University of York, Heslington, York, YO10 5DD, UK ARTICLE INFO ABSTRACT Keywords: Several superfamilies of plasma membrane channels which regulate transmembrane ion flux have also been Auxiliary subunit shown to regulate a multitude of cellular processes, including proliferation and migration. Ion channels are Cancer typically multimeric complexes consisting of conducting subunits and auxiliary, non-conducting subunits. Calcium channel Auxiliary subunits modulate the function of conducting subunits and have putative non-conducting roles, further Chloride channel expanding the repertoire of cellular processes governed by ion channel complexes to processes such as trans- Potassium channel cellular adhesion and gene transcription. Given this expansive influence of ion channels on cellular behaviour it Sodium channel is perhaps no surprise that aberrant ion channel expression is a common occurrence in cancer. This review will − focus on the conducting and non-conducting roles of the auxiliary subunits of various Ca2+,K+,Na+ and Cl channels and the burgeoning evidence linking such auxiliary subunits to cancer. Several subunits are upregu- lated (e.g. Cavβ,Cavγ) and downregulated (e.g. Kvβ) in cancer, while other subunits have been functionally implicated as oncogenes (e.g. Navβ1,Cavα2δ1) and tumour suppressor genes (e.g. CLCA2, KCNE2, BKγ1) based on in vivo studies. The strengthening link between ion channel auxiliary subunits and cancer has exposed these subunits as potential biomarkers and therapeutic targets. -
Oegtp - Epilepsy Test Requisition Lab Use Only: Patient Information
OEGTP - EPILEPSY TEST REQUISITION LAB USE ONLY: PATIENT INFORMATION: Received date: Name: Notes: Address: Date of Birth: YY/MM/DD Sex: M F Health Card No: TEST REQUEST: See page 2 for gene list for each of the panels below Epilepsy Comprehensive panel: 167 genes Childhood Onset Epilepsy panel: 45 genes Focal Epilepsy panel: 14 genes Brain Malformation Epilepsy panel: 44 genes London Health Sciences Centre – (Molecular Genetics) London Health Sciences Centre Progressive Myoclonic Epilepsy panel: 20 genes Actionable Gene Epilepsy panel: 22 genes Early Infantile Epilepsy panel: 51 genes Single gene test: Carrier Testing/ KnownFamily Mutation SAMPLE COLLECTION: Name of index case in the family (include copy of report) Date drawn: YY/MM/DD EDTA blood (lavender top) (5ml at room temp) Affected Unaffected Date of Birth: Relationship to patient: REFERRING PHYSICIAN: Authorized Signature is Required Gene: RefSeq:NM Physician Name (print): Mutation: Signature: Email: REASON FOR REFERRAL: Clinic/Hospital: Diagnostic Testing Address: Clinical Diagnosis: Telephone: Fax: CC report to: Name: Clinical Presentation: Address: Telephone: Fax: Molecular Genetics Laboratory Victoria Hospital, Room B10-123A 800 Commissioners Rd. E. London, Ontario | N6A 5W9 Pathology and Laboratory Medicine Ph: 519-685-8122 | Fax: 519-685-8279 Page 1 of 6 Page OEGTP (2021/05/28) OEGTP - EPILEPSY TEST PANELS Patient Identifier: COMPREHENSIVE EPILEPSY PANEL: 167 Genes ACTB, ACTG1, ADSL, AKT3, ALDH7A1, AMT, AP3B2, ARFGEF2, ARHGEF9, ARV1, ARX, ASAH1, ASNS, ATP1A3, ATP6V0A2, ATP7A, -
Expression Profiling of Ion Channel Genes Predicts Clinical Outcome in Breast Cancer
UCSF UC San Francisco Previously Published Works Title Expression profiling of ion channel genes predicts clinical outcome in breast cancer Permalink https://escholarship.org/uc/item/1zq9j4nw Journal Molecular Cancer, 12(1) ISSN 1476-4598 Authors Ko, Jae-Hong Ko, Eun A Gu, Wanjun et al. Publication Date 2013-09-22 DOI http://dx.doi.org/10.1186/1476-4598-12-106 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Ko et al. Molecular Cancer 2013, 12:106 http://www.molecular-cancer.com/content/12/1/106 RESEARCH Open Access Expression profiling of ion channel genes predicts clinical outcome in breast cancer Jae-Hong Ko1, Eun A Ko2, Wanjun Gu3, Inja Lim1, Hyoweon Bang1* and Tong Zhou4,5* Abstract Background: Ion channels play a critical role in a wide variety of biological processes, including the development of human cancer. However, the overall impact of ion channels on tumorigenicity in breast cancer remains controversial. Methods: We conduct microarray meta-analysis on 280 ion channel genes. We identify candidate ion channels that are implicated in breast cancer based on gene expression profiling. We test the relationship between the expression of ion channel genes and p53 mutation status, ER status, and histological tumor grade in the discovery cohort. A molecular signature consisting of ion channel genes (IC30) is identified by Spearman’s rank correlation test conducted between tumor grade and gene expression. A risk scoring system is developed based on IC30. We test the prognostic power of IC30 in the discovery and seven validation cohorts by both Cox proportional hazard regression and log-rank test. -
Drugs, Herg and Sudden Death A.M
Cell Calcium 35 (2004) 543–547 Drugs, hERG and sudden death A.M. Brown a,b,∗ a MetroHealth Campus, Case Western Reserve University, Cleveland, OH 44128, USA b ChanTest, Inc., 14656 Neo Parkway, Cleveland, OH 44128, USA Received 1 December 2003; accepted 12 January 2004 Abstract Early recognition of potential QT/TdP liability is now an essential component of the drug discovery/drug development program. The hERG assay is an indispensable step and a high-quality assay must accompany any investigational new drug (IND) application. While it is the gold standard at present, the hERG assay is too labor-intensive and too low throughput to be used as a screen early in the discovery/development process. A variety of indirect high throughput screens have been used. © 2004 Elsevier Ltd. All rights reserved. Keywords: Screens; Throughput; hERG; QT; Sudden death Sudden cardiac death due to non-cardiac drugs is the ma- fexofenadine, the active metabolite for which terfenadine is jor safety issue presently facing the pharmaceutical industry a pro-drug, became available. and the agencies that regulate it. In recent years, several TdP is linked to defective repolarization and prolongation blockbuster drugs such as terfenadine (Seldane), cisapride of the QT interval of the EKG; at the cellular level the (Propulsid), grepafloxacin (Raxar) and terodiline have been duration of the cardiac action potential (APD) is prolonged. withdrawn from major markets, other drugs such as sertin- The major membrane currents that might be involved are dole (Serlect) have been withdrawn prior to marketing and shown in Fig. 1. still others such as ziprasidone (Zeldox) have undergone In 1993, Woosley’s lab showed that terfenadine blocked + severe labeling restrictions.