We are primarily interested in determining the mechanisms by which L-type calcium channels, and not other calcium entry routes, influence neuronal plasticity via changes in gene expression and protein synthesis. Specifically, we believe different alpha1 subunits of L-type calcium channels are uniquely responsible for activation of the transcription factors CREB and NFATc4, both of which regulate cellular excitability. The experiments we will use to address this question are organized into three specific aims: 1) Determine the molecular components of (alpha1C that are necessary and sufficient for activation of CREB. 2) Establish whether it is the (alpha1C and/or alpha1D comprised L-type calcium channel that regulates NFATc4 activation. 3) Elucidate the mechanism by which L-type calcium channels regulate NFAT-dependent transcription. Our overall goal is to comprehend why the expression of many genes influencing cell excitability are tightly regulated by calcium entry specifically through L-type calcium channels. Thus, we will gain insight into the mechanisms surrounding a variety of cellular events, including those linked to development, learning and memory, hyperalgesia, drug addiction and aging.
