Molecular basis of NMDA receptor functional diversity

Published on April 2, 2014   43 min
0:00
Hello, my name is Jon Johnson. I'm a professor in the Department of Neuroscience at the University of Pittsburgh. My talk concerns NMDA receptors, a type of glutamate receptor found in most fast excitatory synapses in vertebrate nervous systems. I will describe some of the basic characteristics and functions of NMDA receptors, diversity of NMDA receptor properties, and the molecular basis for NMDA receptor diversity.
0:26
I will start by introducing the function, structure, and some of the salient properties of NMDA receptors.
0:33
NMDA receptors are found at glutamatergic synapses, the most common type of fast excitatory synapse on vertebrate neurons. Glutamate released from the presynaptic terminal of glutamatergic synapses binds to and activates glutamate receptors in the postsynaptic membrane. Typically, there is a mix of several types of glutamate receptors including NMDA receptors in the postsynaptic membrane at each glutamatergic synapse. NMDA receptors are ionotropic glutamate receptors, which are ligand-gated ion channels that incorporate both agonist binding sites and an ion channel into a single molecular complex. All ionotropic glutamate receptors are tetrameric proteins-- that is, proteins composed of four subunits. An ion channel is formed and surrounded by the four subunits.
1:21
There are three types of channel-forming ionotropic glutamate receptors-- NMDA, AMPA, and kainate receptors. All three receptor types can be found in the postsynaptic membrane of glutamatergic synapses as well as at other locations on neurons. It is very common to find NMDA and AMPA receptors co-localized postsynaptically. The subunits that can contribute to each type of glutamate receptor are shown here. The subunits that form NMDA receptors are divided into three groups. A single gene encodes the Glu in one subunit, which exists as eight splice variants. There are four types of Glu in two subunits and two types of Glu in three subunits, each encoded by a separate gene.
2:00
Although AMPA and kainate receptors can form as homotetramers, functional NMDA receptors can only be made as heterotetramers. The GluN1 subunit is required for formation of NMDA receptors. The most commonly expressed NMDA receptors are composed of a combination of GluN1 and GluN2 subunits, probably with two GluN1's and two GluN2's. It is believed that the GluN1 subunits are across from each other and the receptor, as our other GluN2 subunits, resulting in a 1, 2, 1, 2 arrangement around the channel. Many NMDA receptors are diheteromeric-- that is, they are formed from two different types of subunits. The most common diheteromeric receptors are formed from GluN1 and GluN2 subunits. These four NMDA receptor subtypes are shown on the top row of this slide. It's possible also to form diheteromeric NMDA receptors from GluN1 and GluN3 subunits. But their expression in neurons appears to be very limited. NMDA receptors can also be triheteromeric-- that is, formed from three different subunit types. Five examples of triheteromeric NMDA receptors are shown on the bottom row of this slide. Triheteromeric NMDA receptors are widely expressed in the nervous system, and maybe more common than diheteromeric receptors. Characterization of triheteromeric receptors is very challenging because no straightforward method for their study in isolation has been developed, although we do have a limited knowledge of triheteromeric receptor properties based on some ingenious approaches. In this talk, I will focus on the properties of the four diheteromeric NMDA receptor subtypes shown on the top row of this slide.
3:30
A simplified schematic of two NMDA receptor subunits is shown here. Although GluN1 and GluN2 subunits are thought to lie next to each other in a complete receptor, this simple schematic shows a GluN1 and a GluN2 subunit across from each other. The most extracellular region of ionotropic glutamate receptors is called either the N-terminal domain or amino terminal domain, labeled here NTD or ATD. This is a large regulatory region that in some receptor subtypes binds modulatory ligands. Between the NTD and the membrane is a ligand binding domain, or LBD, which binds receptor agonists. The parts of ionotropic glutamate receptors located within the membrane are the M1, M3, and M4 transmembrane regions and the M2 reentered loop. The narrowest part of the ion channels is lined by the M2 reentered loop. Finally, an intracellular C-terminal domain, or CTD, is involved in receptor modulation and binding to intracellular scaffolding molecules. The ligand binding domain of most ionotropic glutamate receptor subunits binds glutamate. However, the ligand binding domains of GluN1 and GluN3 subunits bind the endogenous ligands glycine and D-serine rather than glutamate. As a result, NMDA receptors are the only litigated ion channels that require two different types of agonists molecules for activation. In contrast to glutamate, the source of glycine or D-serine that activates NDMA receptors appears not to be presynaptic vesicles. In some cases, astrocytes may be the source of ligands that bind to the GluN1 subunit. A crystal structure of an AMPA receptor composed of four GluA2 subunits was published in 2009 by Sobolevsky et al. An image of this beautiful structure is shown on the right. The structure shows a nearly complete receptor with only a few regions, such as the C-terminal domain and parts of the M2 reentered loop not included. NMDA receptors probably share many features with this AMPA receptor structure, which represents a great advance in our understanding of ionotropic glutamate receptors.
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Molecular basis of NMDA receptor functional diversity

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