FK506-binding protein 1b/12.6: A key to aging-related hippocampal Ca 2+ dysregulation?

Academic Article

Abstract

  • © 2013 Elsevier B.V. All rights reserved. It has been recognized for some time that the Ca 2+ -dependent slow afterhyperpolarization (sAHP) is larger in hippocampal neurons of aged compared with young animals. In addition, extensive studies since have shown that other Ca 2+ -mediated electrophysiological responses are increased in hippocampus with aging, including Ca 2+ transients, L-type voltage-gated Ca 2+ channel activity, Ca 2+ spike duration and action potential accommodation. Elevated Ca 2+ -induced Ca 2+ release from ryanodine receptors (RyRs) appears to drive amplification of the Ca 2+ responses. Components of this Ca 2+ 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 Ca 2+ 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 Ca 2+ -induced Ca 2+ 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 Ca 2+ 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 Ca 2+ dysregulation in the brain and point to potential new therapeutic targets for counteracting unhealthy brain aging.
  • Authors

    Published In

    Digital Object Identifier (doi)

    Pubmed Id

  • 19845722
  • Author List

  • Gant JC; Blalock EM; Chen KC; Kadish I; Porter NM; Norris CM; Thibault O; Landfield PW
  • Start Page

  • 74
  • End Page

  • 82
  • Volume

  • 739
  • Issue

  • C