Dynamics of Signaling in the NO/cGMP Pathway

了解细胞内信使分子的功能对于完整地解释神经细胞如何交流是至关重要的。神经递质分子激活神经细胞表面的分子受体，引发一系列由细胞内信使精心策划的事件。关键信使是钙离子的浓度，它控制着气态神经递质一氧化氮（NO）的产生。反过来，一氧化氮刺激环核苷酸信使cGMP的产生。钙离子、NO和cGMP共同调节许多生理事件，包括突触传递和膜离子通道的打开。本研究项目的重点是钙离子浓度的动力学，钙离子浓度受钙从细胞内储存室释放和钙离子通过细胞膜流入的影响。更具体地说，实验关注的是培养细胞中由毒蕈碱胆碱能受体激活的内部信号通路。所采用的技术包括电压钳和钙成像；这些与现代分子技术相结合，详细检查钙释放激活，钙内流和cGMP生产中的限速步骤。预计这些实验将极大地促进我们对神经细胞内调节信号的基本细胞机制的理解。

9514421 Thompson Understanding the functioning of messenger molecules inside cells is critical for a complete explanation of how nerve cells communicate. Activation of molecular receptors on the surface of nerve cells by neurotransmitter molecules unleashes a cascade of events, which is orchestrated by the intracellular messengers. The key messenger is the concentration of calcium ions, which controls the production of the gaseous neurotransmitter, nitric oxide (NO). Nitric oxide, in turn, stimulates the production of the cyclic nucleotide messenger, cGMP. Calcium ions, NO, and cGMP together regulate numerous physiological events, including synaptic transmission and the opening of membrane ion channels. The focus of this research project is on the dynamics of calcium ion concentrations, which are affected by calcium release from intracellular storage compartments and by calcium ion inflow through the cell membrane. More specifically, the experiments are concerned with the internal signaling pathway that is activated by muscarinic cholinergic receptors in cultured cells. Techniques employed include the voltage clamp and calcium imaging; these are combined with modern molecular techniques to examine in detail rate-limiting steps in the activation of calcium release, for calcium influx, and in the production of cGMP. It is expected that these experiments will greatly advance our understanding of fundamental cellular mechanisms that regulate signaling within nerve cells.