FK506-binding protein 1b/12.6: A key to aging-related hippocampal Ca2+ dysregulation?

J. C. Gant, E. M. Blalock, K. C. Chen, I. Kadish, N. M. Porter, C. M. Norris, O. Thibault, P. W. Landfield

Research output: Contribution to journalReview articlepeer-review

28 Scopus citations

Abstract

It has been recognized for some time that the Ca2+-dependent slow afterhyperpolarization (sAHP) is larger in hippocampal neurons of aged compared with young animals. In addition, extensive studies since have shown that other Ca2+-mediated electrophysiological responses are increased in hippocampus with aging, including Ca2+ transients, L-type voltage-gated Ca2+ channel activity, Ca2+ spike duration and action potential accommodation. Elevated Ca2+-induced Ca2+ release from ryanodine receptors (RyRs) appears to drive amplification of the Ca2+ responses. Components of this Ca2+ dysregulation phenotype correlate with deficits in cognitive function and plasticity, indicating they may play critical roles in aging-related impairment of brain function. However, the molecular mechanisms underlying aging-related Ca2+ dysregulation are not well understood. FK506-binding proteins 1a and 1b (FKBP1a/1b, also known as FKBP12/12.6) are immunophilin proteins that bind the immunosuppressant drugs FK506 and rapamycin. In muscle cells, FKBP1a/1b also bind RyRs and inhibits Ca2+-induced Ca2+ release, but it is not clear whether FKBPs act similarly in brain cells. Recently, we found that selectively disrupting hippocampal FKBP1b function in young rats, either by microinjecting adeno-associated viral vectors expressing siRNA, or by treatment with rapamycin, increases the sAHP and recapitulates much of the hippocampal Ca2+ dysregulation phenotype. Moreover, in microarray studies, we found FKBP1b gene expression was downregulated in hippocampus of aging rats and early-stage Alzheimer's disease subjects. These results suggest the novel hypothesis that declining FKBP function is a key factor in aging-related Ca2+ dysregulation in the brain and point to potential new therapeutic targets for counteracting unhealthy brain aging.

Original languageEnglish
Pages (from-to)74-82
Number of pages9
JournalEuropean Journal of Pharmacology
Volume739
Issue numberC
DOIs
StatePublished - Sep 15 2014

Bibliographical note

Publisher Copyright:
© 2013 Elsevier B.V. All rights reserved.

Keywords

  • Aging
  • Calcium
  • FKBP1b
  • Ryanodine receptor

ASJC Scopus subject areas

  • Pharmacology

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