Calcium channel modulation by CaBP1 during aging

随着年龄的增长，通过电压门控钙通道(VGCC)内流的钙离子显著影响海马区突触的可塑性，这可能是老年人认知功能减退和记忆丧失的原因之一。VGCC受多种细胞因子的调控，其表达可能会随着年龄的增长而改变。L和P/Q型VGCC均受钙离子感受器钙调蛋白(CaM)的调节，钙调蛋白与这些通道的主要成孔α1亚单位结合。此外，CaM相关蛋白CaBP 1与P/Q型通道的CaM结合域相互作用，但对这些通道产生强烈的钙非依赖性抑制，这与CaM对这些通道的调节不同，令人惊讶。以前的研究表明，与CaBP1相关的钙结合蛋白随着年龄的增长而下调。CABP 1和VGCCs在海马区的细胞和亚细胞定位惊人地相似，突触的可塑性长期以来一直与学习和记忆的控制有关。因此，CaBP1对VGCC的调节可能对衰老大脑中神经元钙信号和神经功能的调节以及潜在的调节失调产生重要影响。这项建议的具体目的是：(1)表征CaBP1和VGCC之间的功能相互作用；(2)确定CABP 1相对于VGCC在海马区的细胞和亚细胞定位；以及(3)确定CABP 1和VGCC之间的相互作用在衰老的大脑中是否发生改变。实现这些目标将加强目前对正常动物和老年动物中神经元VGCC功能的理解。此外，拟议的研究将使未来能够分析与年龄相关的VGCC调制变化的神经生理学后果，这可能揭示替代的药理学策略，以抵消正常衰老和阿尔茨海默病等神经病理疾病造成的认知缺陷。

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.