title: FK506-binding protein 1b/12.6: a key to aging-related hippocampal Ca2+ dysregulation?
abstract: 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.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, 800 Rose St., UKMC Lexington, KY 40536, United States.
authors.forename: J C
authors.initials: JC
authors.lastname: Gant
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, 800 Rose St., UKMC Lexington, KY 40536, United States.
authors.forename: E M
authors.initials: EM
authors.lastname: Blalock
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, 800 Rose St., UKMC Lexington, KY 40536, United States.
authors.forename: K-C
authors.initials: KC
authors.lastname: Chen
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, 800 Rose St., UKMC Lexington, KY 40536, United States.
authors.forename: I
authors.initials: I
authors.lastname: Kadish
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, 800 Rose St., UKMC Lexington, KY 40536, United States.
authors.forename: N M
authors.initials: NM
authors.lastname: Porter
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, 800 Rose St., UKMC Lexington, KY 40536, United States.
authors.forename: C M
authors.initials: CM
authors.lastname: Norris
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, 800 Rose St., UKMC Lexington, KY 40536, United States.
authors.forename: O
authors.initials: O
authors.lastname: Thibault
authors.affiliation: Department of Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine, 800 Rose St., UKMC Lexington, KY 40536, United States. Electronic address: pwland@uky.edu.
authors.forename: P W
authors.initials: PW
authors.lastname: Landfield
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D009474:Neurons / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D022021:Tacrolimus Binding Proteins; C403484:tacrolimus binding protein 1B; D002118:Calcium
keywords: Aging; Calcium; FKBP1b; Ryanodine receptor