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

Academic Article

Abstract

  • It has been recognized for some time that the Ca -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 -mediated electrophysiological responses are increased in hippocampus with aging, including Ca transients, L-type voltage-gated Ca channel activity, Ca spike duration and action potential accommodation. Elevated Ca -induced Ca release from ryanodine receptors (RyRs) appears to drive amplification of the Ca responses. Components of this Ca 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 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 -induced Ca 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 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 dysregulation in the brain and point to potential new therapeutic targets for counteracting unhealthy brain aging. 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+ 2+
  • Authors

    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