Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Submit
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

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

Sharan R. Srinivasan, Haoran Huang, Wei-Chih Chang, Joshua A. Nasburg, Hai M. Nguyen, Tim Strassmaier, Heike Wulff and Vikram G. Shakkottai
Molecular Pharmacology July 2022, 102 (1) 17-28; DOI: https://doi.org/10.1124/molpharm.121.000478
Sharan R. Srinivasan
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Haoran Huang
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Wei-Chih Chang
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joshua A. Nasburg
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hai M. Nguyen
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tim Strassmaier
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Heike Wulff
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Vikram G. Shakkottai
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.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

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-N-(5-chloro-2-cyanophenyl)-3-(trifluoromethyl)benzene-1-sulfonamide (herein renamed BK-20), that exhibited a more potent half-maximal activation of BK current (pAC50 = 4.64) than NS-1619 (pAC50 = 3.7) at a free internal calcium concentration of 270 nM in a heterologous expression system and improved spiking regularity in SCA1 Purkinje neurons. BK-20 had no activity on small-conductance calcium-activated potassium (SK)1–3 channels but interestingly was a potent blocker of the T-type calcium channel, Cav3.1 (IC50 = 1.05 μM). Our work describes both a novel compound for further drug development in disorders with irregular Purkinje spiking and a unique platform for drug discovery in degenerative ataxias.

SIGNIFICANCE STATEMENT Motor impairment associated with altered Purkinje cell spiking due to dysregulation of large-conductance calcium-activated potassium (BK) channel expression and function is a shared feature of disease in many degenerative ataxias. BK channel activators represent an outstanding therapeutic agent for ataxia. We have developed a high-throughput platform to screen for BK channel activators and identified a novel compound that can serve as a template for future drug development for the treatment of these disabling disorders.

Footnotes

    • Received December 15, 2021.
    • Accepted April 7, 2022.
  • This research was supported by National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R25-NS089450-06] (S.R.S.) and [Grant R01-NS085054] (V.G.S.) and by University of Michigan/Michigan Drug Discovery U069310 (S.R.S. and V.G.S.).

  • Tim Strassmaier is employed by Nanion Technologies, the manufacturer of the high-throughput patch clamp instrument SyncroPatch 384PE used in the current study. The authors declare that they have no conflicts of interest with the contents of this article.

  • https://doi.org/10.1124/molpharm.121.000478.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 102 (1)
Molecular Pharmacology
Vol. 102, Issue 1
1 Jul 2022
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Discovery of Novel Activators of Large-Conductance Calcium-Activated Potassium Channels for the Treatment of Cerebellar Ataxia
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

Discovering BK Channel Activators for Treatment of Ataxia

Sharan R. Srinivasan, Haoran Huang, Wei-Chih Chang, Joshua A. Nasburg, Hai M. Nguyen, Tim Strassmaier, Heike Wulff and Vikram G. Shakkottai
Molecular Pharmacology July 1, 2022, 102 (1) 17-28; DOI: https://doi.org/10.1124/molpharm.121.000478

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Research ArticleArticle

Discovering BK Channel Activators for Treatment of Ataxia

Sharan R. Srinivasan, Haoran Huang, Wei-Chih Chang, Joshua A. Nasburg, Hai M. Nguyen, Tim Strassmaier, Heike Wulff and Vikram G. Shakkottai
Molecular Pharmacology July 1, 2022, 102 (1) 17-28; DOI: https://doi.org/10.1124/molpharm.121.000478
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • The binding site for KCI807 in the androgen receptor
  • Fatty acid amide hydrolase in cisplatin nephrotoxicity
  • eCB Signaling System in hiPSC-Derived Neuronal Cultures
Show more Articles

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2023 by the American Society for Pharmacology and Experimental Therapeutics