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

Reduction of Calcineurin Activity in Brain by Antisense Oligonucleotides Leads to Persistent Phosphorylation of τ Protein at Thr181 and Thr231

Timothy D. Garver, Randall L. Kincaid, Richard A. Conn and Melvin L. Billingsley
Molecular Pharmacology April 1999, 55 (4) 632-641;
Timothy D. Garver
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Randall L. Kincaid
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Richard A. Conn
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Melvin L. Billingsley
  • 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

Phosphorylation of τ protein promotes stability of the axonal cytoskeleton; aberrant τ phosphorylation is implicated in the biogenesis of paired helical filaments (PHF) seen in Alzheimer’s disease. Protein kinases and phosphatases that modulate τ phosphorylation have been identified using in vitro techniques; however, the role of these enzymes in vivo has not been determined. We used intraventricular infusions of antisense oligodeoxynucleotides (ODNs) directed against the major brain isoforms of the Ca2+/calmodulin-dependent phosphatase calcineurin to determine how reduced activity of this enzyme would affect τ dephosphorylation. Five-day infusions of antisense ODNs (5 and 10 nmol/day) in rats decreased immunoreactive levels and activity of calcineurin throughout the brain; sense ODNs, scrambled ODNs, and infusion vehicle alone had no effect. When neocortical slices were prepared from antisense ODN-treated rats and incubated for 1 to 2 h in vitro, τ protein remained phosphorylated as determined by using the phosphorylation-sensitive monoclonal antibodies AT-180 (Thr231) and AT-270 (Thr181). In contrast, AT-180 and AT-270 sites were completely dephosphorylated during incubation of neocortical slices from vehicle-infused controls and sense ODN-treated rats. Neocortical slices from antisense-treated rats were incubated with the phosphatase inhibitors okadaic acid (100 nM; 10 μM) and FK-520 (5 μM); these preparations showed enhanced τ phosphorylation, consistent with a significant loss of calcineurin activity. Thus, we conclude that phosphorylation of at least two sites on τ protein, namely, Thr181 and Thr231, is regulated by calcineurin.

Footnotes

  • Send reprint requests to: Dr. Melvin L. Billingsley, Department of Pharmacology, Pennsylvania State University College of Medicine, Milton S. Hershey Medical Center, P.O. Box 850, Hershey PA 17033. E-mail mlb8{at}psu.edu

  • ↵1 Present address: Lineberry Research Associates, Research Triangle Park, NC 27709.

  • This work was supported by grants from the American Health Assistance Foundation Alzheimer Research Program and a Targeted Research Grant from The Alzheimer’s Foundation (M.L.B.) and by an Advanced Predoctoral Fellowship from the Pharmaceutical Manufacturer’s Association Foundation (T.D.G.).

  • Abbreviations:
    PHF
    paired helical filament
    ODN
    oligodeoxynucleotide
    aCSF
    artificial cerebrospinal fluid
    PP1
    protein phosphatase 1
    PP2
    protein phosphatase 2
    • Received October 27, 1998.
    • Accepted January 18, 1999.
  • 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: 55 (4)
Molecular Pharmacology
Vol. 55, Issue 4
1 Apr 1999
  • Table of Contents
  • About the Cover
  • Index by author
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.
Reduction of Calcineurin Activity in Brain by Antisense Oligonucleotides Leads to Persistent Phosphorylation of τ Protein at Thr181 and Thr231
(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

Reduction of Calcineurin Activity in Brain by Antisense Oligonucleotides Leads to Persistent Phosphorylation of τ Protein at Thr181 and Thr231

Timothy D. Garver, Randall L. Kincaid, Richard A. Conn and Melvin L. Billingsley
Molecular Pharmacology April 1, 1999, 55 (4) 632-641;

Citation Manager Formats

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

Share
Research ArticleArticle

Reduction of Calcineurin Activity in Brain by Antisense Oligonucleotides Leads to Persistent Phosphorylation of τ Protein at Thr181 and Thr231

Timothy D. Garver, Randall L. Kincaid, Richard A. Conn and Melvin L. Billingsley
Molecular Pharmacology April 1, 1999, 55 (4) 632-641;
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
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • EIPA, HMA and SMN2 gene regulation
  • Clc-2 has minor role in intestinal Cl- secretion
  • Resveratrol acts as an NR4A1 antagonist in lung cancer.
Show more Article

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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics