Browsing by Subject "NTD domain"

AMPA receptors (AMPARs) are the most numerous synaptic receptors in the hippocampus. Here they take one of the central roles in the expression of long-term potentiation (LTP), the molecular mechanism underlying learning and memory. They belong to the group of glutamate-gated ion channels and have a structure characterized by 4 discrete domains. While the functional roles of C-terminal (CTD), transmembrane (TMD) and ligand-binding (LBD) domains have largely been established, the regulatory capacity - if any - of the N-terminal domain (NTD) remains questionable. In this thesis we used molecular dynamics (MD) simulations to show directly for the first time that AMPA receptor NTD domain can respond to the pH of the surrounding medium. Specifically, we identified a pair of histidine residues in the NTD interface, which are capable of acting as pH sensors - upon acidification of the environment the two histidines become protonated and through electrostatic repulsion destabilize the NTD interface. If experimentally validated, this model could provide a mechanistic explanation of AMPAR clustering in synapses. Due to low affinity for glutamate under physiological conditions, it has been proposed that AMPARs form clusters right underneath glutamate release sites in order to produce sufficiently large postsynaptic depolarizations. Since the lumen of glutamate vesicles is acidic, the presynaptic glutamate release is coupled to transient acidification of the synaptic environment. In our model this acidification is detected by identified interface histidines, which upon protonation cause structural rearrangement of the NTD interface. This rearrangement could lead to formation of interactions either with other AMPARs or synaptic anchor proteins (such as PSD-95), resulting in AMPAR clustering underneath glutamate release sites.