Edward B. Ziff

Biochemistry

Control of Glutamate Receptors at Excitatory Synapses

You may also want to visit my HHMI, NYU School of Medicine and Department of Biochemistry web pages.

Our laboratory studies the regulation of ionotropic glutamate receptors at excitatory synapses in the rat central nervous system. We focus on two subtypes of these receptors, the NMDA and the AMPA receptors. Both subtypes are multisubunited ion channels which are regulated by the neurotransmitter, glutamate. The AMPA receptor provides the majority of fast excitatory transmission and the NMDA receptor, synaptic plasticity. However, the two receptor types are thought to influence each other's function when activity-dependent alterations in synaptic strength take place. Many properties of these receptors at synapses are thought to be controlled by receptor interactions with cytoplasmic proteins. Such interactions cluster receptors at synapses, tether the receptors to regulatory proteins and possibly govern the transport of the receptors to synapses and receptor biochemical properties. To understand receptor regulation, we have cloned proteins that bind to receptor intracellular domains. Our work has disclosed two such proteins. One called ABP (AMPA receptor Binding Protein) binds to the C terminal domain of the AMPA receptor GluR2 subunit via a structure called a PDZ domain. ABP has 6 PDZ domains. NMDA receptors are known to bind to a related protein, PSD-95, also through a PDZ domain interaction. Our work shows that ABP, and a related protein, GRIP (Glutamate Receptor Interacting Protein) can form homo and heteromultimers as well as bind AMPA receptors. PSD-95 also multimerizes, an action which is thought to cluster NMDA receptors at synapses. Our work indicates that ABP/GRIP and PSD-95 form distinct scaffolds at synapses that may separately govern the localization and control of AMPA and NMDA receptors. We also find that the chaperonin NSF binds to the GluR2 C terminus. We have defined structural and biochemical properties of the NSF-GluR2 interaction. Based on the known role of NSF in the mechanism of synaptic vesicle fusion, we are testing a model in which NSF mediates the exchange of proteins that bind to GluR2 C terminal domain. Our work suggests that aspects of synaptic plasticity dependent upon AMPA receptors may be dictated by protein interactions with receptor cytoplasmic domains.

Email: edward.ziff@med.nyu.edu

Representative Publications

Osten, P., Srivastava, S., Inman, G.J., Vilim, F.S., Lee, L.M., Hanson, P.I., Einheber, S., Milner, T.A. and Ziff, E.B. (1998). The AMPA receptor GluR2 C-terminus can mediate reversible, ATP-dependent interaction with NSF and , SNAPS. Neuron 21 , 99-110.

Srivastava, S., Vilim, F.S., Khatri, L., Inman, G., States, B., Daly, C., Osten, P., DeSouza, S., Abagyan, R. and Ziff, E.B. (1998). Novel anchorage of GluR2/3 to the postsynaptic density by the AMPA receptor-binding protein ABP. Neuron 21, 581-591.

Osten, P., Khatri, L., Perez, J.L., Kohr, G., Daly, C., Schulz, T.W., Wensky, A., Lee, L. and Ziff, E.B. (2000). Mutagenesis reveals a role for ABP/GRIP binding to GluR2 in synaptic surface accumulation of the AMPA receptor. Neuron 27, 313-325.

Perez, J.L., Khatri, L., Chang, C., Srivastava, S., Osten, P. and Ziff, E.B. (2001). PICK1 targets activated protein kinase C alpha to AMPA receptor clusters in spines of hippocampal neurons and reduces surface levels of AMPA-type glutamate receptor subunit 2. J. Neurosci. 21(15), 5417-28.