Age-related alterations in Ca 2+ influx through voltage-gated Ca 2+ channels (VGCCs) significantly affect synaptic plasticity in the hippocampus, which may contribute to the cognitive decline and memory loss in elderly humans. VGCCs are modulated by various cellular factors, the expression of which may change with aging. Both L- and P/Q-type VGCCs are regulated by the Ca2+-sensor calmodulin (CAM), which binds to the main pore-forming alpha1 subunit of these channels. In addition, CaBP 1, a protein related to CaM, interacts with the CaM-binding domain of P/Q-type channels but causes a strong, Ca2+-independent inhibition of these channels that is surprisingly different from their modulation by CaM. Previous studies indicate that Ca2+-binding proteins related to CaBP1 are down-regulated with age. The cellular and subcellular localization of CaBP 1 and VGCCs is strikingly similar in the hippocampus, where synaptic plasticity has long been implicated in the control of learning and memory. Therefore, the modulation of VGCCs by CaBP1 may critically influence how neuronal Ca 2+ signals and neurological functions are regulated and potentially dysregulated in the aging brain.
The specific aims of this proposal are to: (1) characterize the functional interactions between CaBP1 and VGCCs; (2) define the cellular and subcellular localization of CaBP 1 with respect to VGCCs in the hippocampus ; and (3) determine if interactions between CaBP 1 and VGCCs are altered in the aging brain. Accomplishing these objectives will strengthen current understanding of the function of neuronal VGCCs in both normal and aged animals. In addition, the proposed research will permit future analyses of the neurophysiological consequences of age-related changes in VGCC modulation, which may reveal alternative pharmacological strategies to offset cognitive deficits resulting from normal aging and neuropathological conditions such as Alzheimer's disease.
| Zhou, Hong; Yu, Kuai; McCoy, Kelly L et al. (2005) Molecular mechanism for divergent regulation of Cav1.2 Ca2+ channels by calmodulin and Ca2+-binding protein-1. J Biol Chem 280:29612-9 |
| Zhou, Hong; Kim, Seong-Ah; Kirk, Elizabeth A et al. (2004) Ca2+-binding protein-1 facilitates and forms a postsynaptic complex with Cav1.2 (L-type) Ca2+ channels. J Neurosci 24:4698-708 |
