The goal of this proposal is foster the development in five years of a productive scientist performing independent research on signal transduction and gene expression in vascular tissue. It will focus on studying how voltage-gated Ca2+ channels regulate gene expression in vascular smooth muscle cells (VSMCs). This will address clinically important issues such as vascular remodeling, which occurs in response to stimuli like chronic hypertension or endothelial injury, and results in VSMC hypertrophy and hyperplasia. Previous work has shown that Ca2+ entry at the cell surface can regulate VSMC growth and proliferation. It has recently been demonstrated that, in hippocampal neurons, activation of L-type Ca2+ channels can lead to phosphorylation of the nuclear transcription factor CREB, suggesting a pathway by which Ca2+ entry can lead to nuclear events. The preliminary studies demonstrate that Ca2+ entry in VSMCs can also lead to CREB phosphorylation. In this application, the following three specific aims will be addressed: 1. The location and mode of Ca2+ entry that leads to gene expression in VSMCs will be determined. 2. The downstream transcriptional events triggered by Ca2+ entry in VSMCs will be explored. 3. The intermediates along the pathway by which Ca2+ entry leads to gene expression in VSMCs will be defined. These questions will be approached with a powerful combination of techniques, including patch clamp electrophysiology of single smooth muscle cells, immunocytochemistry, molecular biology and real time-imaging of Ca2+ and calmodulin distributions.
| Hudmon, Andy; Schulman, Howard; Kim, James et al. (2005) CaMKII tethers to L-type Ca2+ channels, establishing a local and dedicated integrator of Ca2+ signals for facilitation. J Cell Biol 171:537-47 |
| Pitt, G S; Zuhlke, R D; Hudmon, A et al. (2001) Molecular basis of calmodulin tethering and Ca2+-dependent inactivation of L-type Ca2+ channels. J Biol Chem 276:30794-802 |
| Zuhlke, R D; Pitt, G S; Tsien, R W et al. (2000) Ca2+-sensitive inactivation and facilitation of L-type Ca2+ channels both depend on specific amino acid residues in a consensus calmodulin-binding motif in the(alpha)1C subunit. J Biol Chem 275:21121-9 |
