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PMID: 11958864 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Calcineurin enhances L-type Ca(2+) channel activity in hippocampal neurons: increased effect with age in culture.

Neuroscience ·Vol. 110 ·No. 2 ·2002-00-00 ·Pages 213-25

Norris CM, Blalock EM, Chen KC, Porter NM, Landfield PW

Abstract

The Ca(2+)/calmodulin-dependent protein phosphatase, calcineurin, modulates a number of key Ca(2+) signaling pathways in neurons, and has been implicated in Ca(2+)-dependent negative feedback inactivation of N-methyl-D-aspartate receptors and voltage-sensitive Ca(2+) channels. In contrast, we report here that three mechanistically disparate calcineurin inhibitors, FK-506, cyclosporin A, and the calcineurin autoinhibitory peptide, inhibited high-voltage-activated Ca(2+) channel currents by up to 40% in cultured hippocampal neurons, suggesting that calcineurin acts to enhance Ca(2+) currents. This effect occurred with Ba(2+) or Ca(2+) as charge carrier, and with or without intracellular Ca(2+) buffered by EGTA. Ca(2+)-dependent inactivation of Ca(2+) channels was not affected by FK-506. The immunosuppressant, rapamycin, and the protein phosphatase 1/2A inhibitor, okadaic acid, did not decrease Ca(2+) channel current, showing specificity for effects on calcineurin. Blockade of L-type Ca(2+) channels with nimodipine fully negated the effect of FK-506 on Ca(2+) channel current, while blockade of N-, and P-/Q-type Ca(2+) channels enhanced FK-506-mediated inhibition of the remaining L-type-enriched current. FK-506 also inhibited substantially more Ca(2+) channel current in 4-week-old vs. 2-week-old cultures, an effect paralleled by an increase in calcineurin A mRNA levels. These studies provide the first evidence that calcineurin selectively enhances L-type Ca(2+) channel activity in neurons. Moreover, this action appears to be increased concomitantly with the well-characterized increase in L-type Ca(2+) channel availability in hippocampal neurons with age-in-culture.

MeSH Terms
Aging/metabolism Animals Apoptosis Regulatory Proteins Calcineurin/genetics,metabolism Calcineurin Inhibitors Calcium Channel Blockers/pharmacology Calcium Channels, L-Type/drug effects,metabolism Calcium Signaling/drug effects,physiology Carrier Proteins/pharmacology Cell Differentiation/drug effects,physiology Cells, Cultured Chelating Agents/pharmacology Cyclosporine/pharmacology Female Fetus Hippocampus/drug effects,growth & development,metabolism Immunosuppressive Agents/pharmacology Membrane Potentials/drug effects,physiology Neurons/drug effects,metabolism Phosphoprotein Phosphatases/antagonists & inhibitors,metabolism Pregnancy Protein Phosphatase 1 RNA, Messenger/drug effects,metabolism Rats Rats, Sprague-Dawley Tacrolimus/pharmacology Tacrolimus Binding Protein 1A/pharmacology
Chemicals
Apoptosis Regulatory Proteins Cabin1 protein, rat Calcineurin Inhibitors Calcium Channel Blockers Calcium Channels, L-Type Carrier Proteins Chelating Agents Immunosuppressive Agents RNA, Messenger Cyclosporine Calcineurin Phosphoprotein Phosphatases Protein Phosphatase 1 Tacrolimus Binding Protein 1A Tacrolimus
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Norris C M
Department of Molecular and Biomedical Pharmacology, College of Medicine, MS-310 UKMC, University of Kentucky, Lexington, KY 40536-0298, USA. cnorr2@pop.uky.edu
Blalock E M
Chen K-C
Porter N M
Landfield P W
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Article Info
Journal
Neuroscience
Abbr.
Neuroscience
ISSN
0306-4522
DOI
10.1016/s0306-4522(01)00574-7
Email
cnorr2@pop.uky.edu
Published
2002-00-00
Pages
213-25
Language
English
Region
United States
NLM ID
7605074
PMCID
PMC1473990
Subset
IM
Grants
NIA NIH HHS · AG10836 · United States
NIA NIH HHS · AG00242 · United States
NIA NIH HHS · 1F32 AG05903 · United States
NIA NIH HHS · AG04542 · United States
NIA NIH HHS · T32 AG000242 · United States
NIA NIH HHS · P01 AG010836 · United States
NIA NIH HHS · R37 AG004542 · United States
NIA NIH HHS · F32 AG005903 · United States
External Links
PubMed source DOI: 10.1016/s0306-4522(01)00574-7 PMC Full Text View journal details
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