Investigating the Mechanism of Substrate Uptake and Release in the Glutamate Transporter Homologue GltPh through Metadynamics Simulations

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• 作者：Giovanni Grazioso ; Vittorio Limongelli ; Davide Branduardi ; Ettore Novellino ; Carlo De Micheli ; Andrea Cavalli ; Michele Parrinello
• 刊名：The Journal of the American Chemical Society
• 出版年：2012
• 出版时间：January 11, 2012
• 年：2012
• 卷：134
• 期：1
• 页码：453-463
• 全文大小：1231K
• 年卷期：v.134,no.1(January 11, 2012)
• ISSN：1520-5126

文摘

A homeostatic concentration of glutamate in the synaptic cleft ensures a correct signal transduction along the neuronal network. An unbalance in this concentration can lead to neuronal death and to severe neurodegenerative diseases such as Alzheimer鈥檚 or Parkinson鈥檚. Glutamate transporters play a crucial role in this respect because they are responsible for the reuptake of the neurotransmitter from the synaptic cleft, thus controlling the glutamate concentration. Understanding the molecular mechanism of this transporter can provide the possibility of an exogenous control. Structural studies have shown that this transporter can assume at least three conformations, thus suggesting a pronounced dynamical behavior. However, some intermediate states that lead to the substrate internalization have not been characterized and many aspects of the transporter mechanism still remain unclear. Here, using metadynamics simulations, we investigate the substrate uptake from the synaptic cleft and its release in the intracellular medium. In addition, we focus on the role of ions and substrate during these processes and on the stability of the different conformations assumed by the transporter. The present dynamical results can complement available X-ray data and provide a thorough description of the entire process of substrate uptake, internalization, and release.