2002 |
Lee, Amy |
R03Activity Code Description: To provide research support specifically limited in time and amount for studies in categorical program areas. Small grants provide flexibility for initiating studies which are generally for preliminary short-term projects and are non-renewable. |
Calcium Channel Modulation by Cabp1 During Aging
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.
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2003 — 2007 |
Lee, Amy |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Regulation of Neuronal Calcium Channels by Cabp1
DESCRIPTION (provided by applicant): Ca+ entry through Cav2.1 (P/Q-type) channels initiates neurotransmitter release at most central synapses. Because small changes in intracellular Ca2+ can significantly alter synaptic efficacy, regulation of presynaptic Ca/v2.1 channels can powerfully influence processes of information transfer and storage in the brain. Ca/v2.1 channels undergo a feedback regulation by Ca2+ mediated by calmodulin (CaM) binding to the pore-forming alpha1-2.1 subunit of these channels. CaBP1 is representative of a family of neuronal Ca2+-binding proteins (NCBPs) that are related to CaM, but are expressed primarily in neurons. CaBP1 also binds to alpha1-2.1, but has surprisingly different effects than CaM in regulating Ca/v2.1 function. A splice variant of CaBP1, caldendrin, also associates with Cav2.1 channels both in transfected cells and in the brain. Therefore, presynaptic Ca2+ signals and synaptic strength may depend on the differential modulation of Cav2.1 by CaBP1, CaM, or other NCBPs. The goal of this application is to characterize the molecular mechanisms and neurobiological significance of Cav/2.1 modulation by CaBP1. Accomplishing this objective may resolve longstanding questions regarding the diversity of Ca/v2.1 channels in the brain, and suggest alternative therapeutic strategies for treating disorders linked to genetic defects in Cav2.1 such as familial hemiplegic migraine, spinocerebellar ataxia, and absence epilepsy. Molecular biology, immunochemistry, and electrophysiology will be used to address four specific aims: (1) to define the molecular determinants in alpha1-2.1 for binding to CaBP1 and CaM; (2) to determine how structural differences between CaBP1 and CaM affect interactions with Ca/v2.1; (3) to characterize the effect of CaBP1 on the pharmacological properties of Ca/v2.1; and (4) to compare Ca/v2.1 regulation by CaBP1 and caldendrin and co-localization of these proteins in the brain. These studies may reveal how other NCBPs could interact with target molecules thought to be regulated primarily by CaM, which may illuminate novel mechanisms controlling the development, plasticity, and ultimately, the behavioral output of the nervous system
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