Calcineurin enhances L-type Ca2+ channel activity in hippocampal neurons: Increased effect with age in culture

C. M. Norris, E. M. Blalock, K. C. Chen, N. M. Porter, P. W. Landfield

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

Abstract

The Ca2+/calmodulin-dependent protein phosphatase, calcineurin, modulates a number of key Ca2+ signaling pathways in neurons, and has been implicated in Ca2+-dependent negative feedback inactivation of N-methyl-D-aspartate receptors and voltage-sensitive Ca2+ 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 Ca2+ channel currents by up to 40% in cultured hippocampal neurons, suggesting that calcineurin acts to enhance Ca2+ currents. This effect occurred with Ba2+ or Ca2+ as charge carrier, and with or without intracellular Ca2+ buffered by EGTA. Ca2+-dependent inactivation of Ca2+ channels was not affected by FK-506. The immunosuppressant, rapamycin, and the protein phosphatase 1/2A inhibitor, okadaic acid, did not decrease Ca2+ channel current, showing specificity for effects on calcineurin. Blockade of L-type Ca2+ channels with nimodipine fully negated the effect of FK-506 on Ca2+ channel current, while blockade of N-, and P-/Q-type Ca2+ channels enhanced FK-506-mediated inhibition of the remaining L-type-enriched current. FK-506 also inhibited substantially more Ca2+ 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 Ca2+ channel activity in neurons. Moreover, this action appears to be increased concomitantly with the well-characterized increase in L-type Ca2+ channel availability in hippocampal neurons with age-in-culture.

Original languageEnglish
Pages (from-to)213-225
Number of pages13
JournalNeuroscience
Volume110
Issue number2
DOIs
StatePublished - Mar 12 2002

Bibliographical note

Funding Information:
This work was supported in part by Grants from the National Institute on Aging (AG04542, AG10836) and Training Grants (AG00242 and 1F32 AG05903). We wish to thank Elsie Barr, Janice Staton, and Veronique Thibault for important technical assistance, and Kelley Secrest and Judy Hower for excellent assistance with the manuscript.

Keywords

  • Aging
  • Ca channel currents
  • Conotoxins
  • Cyclosporin A
  • FK-506
  • Nimodipine
  • Protein phosphatase

ASJC Scopus subject areas

  • Neuroscience (all)

Fingerprint

Dive into the research topics of 'Calcineurin enhances L-type Ca2+ channel activity in hippocampal neurons: Increased effect with age in culture'. Together they form a unique fingerprint.

Cite this