Discovery of Novel Activators of Large-Conductance Calcium-Activated Potassium Channels for the Treatment of Cerebellar Ataxia.

Animals Ataxia Calcium / metabolism Cerebellar Ataxia / drug therapy Large-Conductance Calcium-Activated Potassium Channels Mice Potassium / metabolism Potassium Channels, Calcium-Activated Spinocerebellar Ataxias / metabolism

Journal

Molecular pharmacology
ISSN: 1521-0111
Titre abrégé: Mol Pharmacol
Pays: United States
ID NLM: 0035623

Informations de publication

Date de publication:
07 2022
Historique:
received: 15 12 2021
accepted: 07 04 2022
pubmed: 1 5 2022
medline: 12 7 2022
entrez: 30 4 2022
Statut: ppublish

Résumé

Impaired cerebellar Purkinje neuron firing resulting from reduced expression of large-conductance calcium-activated potassium (BK) channels is a consistent feature in models of inherited neurodegenerative spinocerebellar ataxia (SCA). Restoring BK channel expression improves motor function and delays cerebellar degeneration, indicating that BK channels are an attractive therapeutic target. Current BK channel activators lack specificity and potency and are therefore poor templates for future drug development. We implemented an automated patch clamp platform for high-throughput drug discovery of BK channel activators using the Nanion SyncroPatch 384PE system. We screened over 15,000 compounds for their ability to increase BK channel current amplitude under conditions of lower intracellular calcium that is present in disease. We identified several novel BK channel activators that were then retested on the SyncroPatch 384PE to generate concentration-response curves (CRCs). Compounds with favorable CRCs were subsequently tested for their ability to improve irregular cerebellar Purkinje neuron spiking, characteristic of BK channel dysfunction in SCA1 mice. We identified a novel BK channel activator, 4-chloro-

Identifiants

DOI: 10.1124/molpharm.121.000478 PMID: 35489717 PMC: PMC9341255
pubmed: 35489717
pii: molpharm.121.000478
doi: 10.1124/molpharm.121.000478
pmc: PMC9341255
doi:

Substances chimiques

Large-Conductance Calcium-Activated Potassium Channels 0
Potassium Channels, Calcium-Activated 0
Potassium RWP5GA015D
Calcium SY7Q814VUP

Types de publication

Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural

Langues

eng

Sous-ensembles de citation

IM

Pagination

438-449

Subventions

Organisme : NINDS NIH HHS
ID : R01 NS085054
Pays : United States
Organisme : NINDS NIH HHS
ID : R25 NS089450
Pays : United States
Organisme : NIH HHS
ID : S10 OD025203
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM099608
Pays : United States

Informations de copyright

Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.

Références

Nat Neurosci. 2006 Mar;9(3):389-97
pubmed: 16474392
J Neurosci. 1999 Mar 1;19(5):1663-74
pubmed: 10024353
J Biomol Screen. 2004 Dec;9(8):671-7
pubmed: 15634793
Front Cell Neurosci. 2021 Jul 01;15:683769
pubmed: 34276309
Biochim Biophys Acta. 2004 Oct 11;1665(1-2):1-5
pubmed: 15471565
Neurol Clin. 2013 Nov;31(4):987-1007
pubmed: 24176420
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5562-7
pubmed: 10792058
J Neurosci. 2004 Apr 7;24(14):3537-42
pubmed: 15071101
Chem Biol. 2012 Oct 26;19(10):1340-53
pubmed: 23102227
Neuron. 2020 Feb 19;105(4):630-644.e9
pubmed: 31859031
Sci Rep. 2016 Jul 06;6:29489
pubmed: 27381005
Ann Clin Transl Neurol. 2018 Jan 22;5(3):297-314
pubmed: 29560375
Hum Mol Genet. 2019 Sep 1;28(17):2937-2951
pubmed: 31152168
Mov Disord. 2021 Mar;36(3):622-631
pubmed: 33151010
Nat Med. 2001 Apr;7(4):471-7
pubmed: 11283675
J Neurosci. 2011 Sep 7;31(36):13002-14
pubmed: 21900579
Brain. 2018 Jul 1;141(7):1998-2013
pubmed: 29878067
Channels (Austin). 2021 Dec;15(1):447-464
pubmed: 34224328
Science. 1993 Jul 9;261(5118):221-4
pubmed: 7687074
Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9200-5
pubmed: 8799178
Neuron. 2002 Jun 13;34(6):905-19
pubmed: 12086639
J Biol Chem. 2000 Mar 3;275(9):6453-61
pubmed: 10692449
Methods Mol Biol. 2018;1684:105-114
pubmed: 29058187
J Neurosci. 2015 Aug 12;35(32):11292-307
pubmed: 26269637
Eur J Pharmacol. 1994 Jan 4;251(1):53-9
pubmed: 8137869
Hum Mol Genet. 2020 Nov 25;29(19):3249-3265
pubmed: 32964235
FEBS Lett. 2000 May 26;474(1):99-106
pubmed: 10828459
Lancet Neurol. 2010 Sep;9(9):885-94
pubmed: 20723845
Cell Signal. 1994 Nov;6(8):861-70
pubmed: 7718406
Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9474-8
pubmed: 15194823
Neuroscience. 2009 Sep 15;162(4):989-1000
pubmed: 19446607
PLoS One. 2018 May 30;13(5):e0198040
pubmed: 29847609
Hum Mol Genet. 2017 Oct 15;26(20):3935-3945
pubmed: 29016852

Auteurs

Sharan R Srinivasan (SR)

Brigham and Women's Hospital, Department of Neurology, Boston, Massachusetts (S.R.S.); University of Texas Southwestern Medical Center, Department of Neurology, Dallas, Texas (H.H., V.G.S.); University of Michigan, Department of Neurology, Ann Arbor, Michigan (S.R.S., W.-C.C.); University of California, Davis, Department of Pharmacology, Davis, California (J.A.N., H.M.N., H.W.); and Nanion Technologies, Munich, Germany (T.S.).

Haoran Huang (H)

Brigham and Women's Hospital, Department of Neurology, Boston, Massachusetts (S.R.S.); University of Texas Southwestern Medical Center, Department of Neurology, Dallas, Texas (H.H., V.G.S.); University of Michigan, Department of Neurology, Ann Arbor, Michigan (S.R.S., W.-C.C.); University of California, Davis, Department of Pharmacology, Davis, California (J.A.N., H.M.N., H.W.); and Nanion Technologies, Munich, Germany (T.S.).

Wei-Chih Chang (WC)

Brigham and Women's Hospital, Department of Neurology, Boston, Massachusetts (S.R.S.); University of Texas Southwestern Medical Center, Department of Neurology, Dallas, Texas (H.H., V.G.S.); University of Michigan, Department of Neurology, Ann Arbor, Michigan (S.R.S., W.-C.C.); University of California, Davis, Department of Pharmacology, Davis, California (J.A.N., H.M.N., H.W.); and Nanion Technologies, Munich, Germany (T.S.).

Joshua A Nasburg (JA)

Brigham and Women's Hospital, Department of Neurology, Boston, Massachusetts (S.R.S.); University of Texas Southwestern Medical Center, Department of Neurology, Dallas, Texas (H.H., V.G.S.); University of Michigan, Department of Neurology, Ann Arbor, Michigan (S.R.S., W.-C.C.); University of California, Davis, Department of Pharmacology, Davis, California (J.A.N., H.M.N., H.W.); and Nanion Technologies, Munich, Germany (T.S.).

Hai M Nguyen (HM)

Brigham and Women's Hospital, Department of Neurology, Boston, Massachusetts (S.R.S.); University of Texas Southwestern Medical Center, Department of Neurology, Dallas, Texas (H.H., V.G.S.); University of Michigan, Department of Neurology, Ann Arbor, Michigan (S.R.S., W.-C.C.); University of California, Davis, Department of Pharmacology, Davis, California (J.A.N., H.M.N., H.W.); and Nanion Technologies, Munich, Germany (T.S.).

Tim Strassmaier (T)

Brigham and Women's Hospital, Department of Neurology, Boston, Massachusetts (S.R.S.); University of Texas Southwestern Medical Center, Department of Neurology, Dallas, Texas (H.H., V.G.S.); University of Michigan, Department of Neurology, Ann Arbor, Michigan (S.R.S., W.-C.C.); University of California, Davis, Department of Pharmacology, Davis, California (J.A.N., H.M.N., H.W.); and Nanion Technologies, Munich, Germany (T.S.).

Heike Wulff (H)

Brigham and Women's Hospital, Department of Neurology, Boston, Massachusetts (S.R.S.); University of Texas Southwestern Medical Center, Department of Neurology, Dallas, Texas (H.H., V.G.S.); University of Michigan, Department of Neurology, Ann Arbor, Michigan (S.R.S., W.-C.C.); University of California, Davis, Department of Pharmacology, Davis, California (J.A.N., H.M.N., H.W.); and Nanion Technologies, Munich, Germany (T.S.).

Vikram G Shakkottai (VG)

Brigham and Women's Hospital, Department of Neurology, Boston, Massachusetts (S.R.S.); University of Texas Southwestern Medical Center, Department of Neurology, Dallas, Texas (H.H., V.G.S.); University of Michigan, Department of Neurology, Ann Arbor, Michigan (S.R.S., W.-C.C.); University of California, Davis, Department of Pharmacology, Davis, California (J.A.N., H.M.N., H.W.); and Nanion Technologies, Munich, Germany (T.S.) Vikram.Shakkottai@UTSouthwestern.edu.

Articles similaires

Evaluating the efficacy of telesurgery with dual console SSI Mantra Surgical Robotic System: experiment on animal model and clinical trials.

Sudhir Prem Srivastava, Vishwajyoti Pascual Srivastava, Avinesh Singh et al.
1.00
Robotic Surgical Procedures Animals Humans Telemedicine Models, Animal

Odour generalisation and detection dog training.

Lyn Caldicott, Thomas W Pike, Helen E Zulch et al.
1.00
Animals Odorants Dogs Generalization, Psychological Smell

FBXO22 inhibits colitis and colorectal carcinogenesis by regulating the degradation of the S2448-phosphorylated form of mTOR.

Minle Li, Xuan Chen, Pengfei Qu et al.
1.00
Animals TOR Serine-Threonine Kinases Colorectal Neoplasms Colitis Mice

Use of organic material provided by an automatic enrichment device by weaner pigs and its influence on tail lesions.

Philipp Heseker, Jeanette Probst, Stefanie Ammer et al.
1.00
Animals Tail Swine Behavior, Animal Animal Husbandry

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Discovery of Novel Activators of...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Manifestations neurologiques › Dyskinésies › Ataxie › Discovery of Novel Activators of...
questionsmedicales.fr › Facteurs biologiques › Facteurs de la coagulation sanguine › Calcium › Discovery of Novel Activators of...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Manifestations neurologiques › Dyskinésies › Ataxie › Ataxie cérébelleuse › Discovery of Novel Activators of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Canaux ioniques › Canaux potassiques › Canaux potassiques calcium-dépendants › Canaux potassiques calcium-dépendants de grande conductance › Discovery of Novel Activators of...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Discovery of Novel Activators of...
questionsmedicales.fr › Produits chimiques inorganiques › Métaux › Métaux légers › Potassium › Discovery of Novel Activators of...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines de transport membranaire › Canaux ioniques › Canaux potassiques › Canaux potassiques calcium-dépendants › Discovery of Novel Activators of...
questionsmedicales.fr › Malformations et maladies congénitales, héréditaires et néonatales › Maladies génétiques congénitales › Maladies neurodégénératives héréditaires › Dégénérescences spinocérébelleuses › Ataxies spinocérébelleuses › Discovery of Novel Activators of...