Ca2+ signals in the nervous system mediate a remarkable variety of cellular functions, including neurotransmitter release, membrane excitability, and proliferation. To control the dynamic features of the signals mediated by this multifunctional messenger and generate specificity, neurons are endowed with a large repertoire of ion channels, pumps, and cellular organelles that work together to sculpt Ca2+ signals. In this repertoire, one of the least understood is the store-operated channel (SOC). SOCs, defined as channels in the plasma membrane that open in response to depletion of Ca2+ from the endoplasmic reticulum (ER), are a widespread mechanism for triggering Ca2+ influx into the cell. In the nervous system, SOCs are known to influence neurotransmitter release and synaptic plasticity, and aberrant signaling involving SOCs is associated with Alzheimer's disease. However, very little is known about the basic properties of neuronal SOCs and the mechanisms linking store depletion to channel activation. The long-term goals of this work are to understand the biophysical characteristics, molecular basis, and functional organization of neuronal SOCs, to identify stimuli that trigger their activation, and to elucidate the downstream consequences of their activation for neuronal function. Recent advances in fluorescent calcium indicators and microscopy provide an opportunity to gain insight into the nature of the SOC activation process. The overall thrust of present proposal is to exploit new tools to probe the store-operated Ca2+ signaling network in neurons, which is comprised of SOCs and the ER, and to explore downstream consequences of this signaling for gene expression. Our immediate objectives are: (1) Define the biophysical properties of neuronal SOCs using patch-clamp electrophysiology. (2) Define the ER Ca2+-dependence of SOC activation by employing cameleon to measure ER Ca2+ signals. How does this compare to the ER Ca2+-dependence of the activation of STIM1, a candidate molecule for the Ca2+ sensor that communicates information about [Ca2+]ER to SOCs? (3) Investigate the role of SOCs in initiating Ca2+-dependent gene expression mediated by the transcription factor, NFAT. Recent work indicates that NFAT is involved in several essential functions such as axonal outgrowth, neuronal survival, and synapse plasticity. An improved understanding of the biophysical properties, activation mechanisms, and functions of SOCs in the nervous system could ultimately reveal novel check points for the regulation of neuronal function by Ca2+, leading to new strategies for the prevention and treatment of diseases such as Alzheimer's disease. ? ?
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