Calcineurin links Ca2+ dysregulation with brain aging.
Brain aging is associated with altered Ca(2+) regulation. However, many Ca(2+) signal transduction mechanisms have not been explored in the aged brain. Here, we report that cytosolic expression and activity of the Ca(2+)-dependent protein phosphatase calcineurin (CaN) increases in the hippocampus during aging. CaN changes were paralleled by increased activation, but not expression, of CaN-regulated protein phosphatase 1 and a reduction in the phosphorylation state of CaN substrates involved in cell survival (i.e., Bcl-2-associated death protein and cAMP response element-binding protein). The age-related increase in CaN activity was not attributable to the inability of CaN to translocate to the membrane and was reduced by blocking L-type Ca(2+) channels. Finally, increased CaN activity correlated with memory function as measured with the Morris water escape task. The results suggest that altered regulation of CaN is one of the processes that could link Ca(2+) dyshomeostasis to age-related changes in neural function and cognition.
Foster
T C
TC
Department of Molecular and Biomedical Pharmacology, University of Kentucky, College of Medicine, Lexington, Kentucky 40536, USA. tfoster@pop.uky.edu
Sharrow
K M
KM
Masse
J R
JR
Norris
C M
CM
Kumar
A
A
D000375:Aging / Q000378:metabolism*; D000818:Animals; D019703:Calcineurin / Q000032:analysis / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism; D003463:Cues; D017362:Cyclic AMP Response Element-Binding Protein / Q000032:analysis / Q000378:metabolism; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D004924:Escape Reaction / Q000502:physiology; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008568:Memory / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D051381:Rats; D011916:Rats, Inbred F344; D011930:Reaction Time / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D051025:bcl-Associated Death Protein
C494821:Bad protein, rat; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D051025:bcl-Associated Death Protein; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D002118:Calcium