B.S. Stony Brook University, 2005
Ph.D. Neuroscience, 2011
Year Medical Student
Lonnie Wollmuth, Ph.D.
Department: Neurobiology & Behavior
Graduate Program: Neuroscience
Specific Sites within the Ligand-Binding Domain and Ion Channel
Linkers Modulate NMDA Receptor Gating
Priya Borker and Lonnie P. Wollmuth2
Graduate Program in Neuroscience, Department of Neurobiology and Behavior,
State University of New York at Stony Brook, Stony Brook, New York 11794-5230
in the NMDA receptor is initiated in the extracellular ligand-binding
domain (LBD) and is ultimately propagated via three linkers—S1-M1,
M3-S2, and S2-M4 —to the ion channel. M3-S2 directly couples LBD
movements into channel gating, but the functional and structural contributions
of S1-M1 and S2-M4 to the overall gating process are unknown. A scan
of substituted cysteines in and around the NMDA receptor S1-M1 and S2-M4
with a bulky cysteine-reactive reagent identified numerous posi- tions
that showed potentiation of glutamate-activated as well as leak currents.
As indexed by MK801 (dizocilpine hydrogen maleate), an open channel
blocker, this potentiation was attributable to an increase in open probability,
an interpretation con- firmed for a subset of positions with single-channel
recordings. The magnitude of this gating effect, acting through S1-M1
or S2-M4, was dependent on the intrinsic gating properties of the NMDA
receptors, being more effective in the inherently low open probability
GluN2C- than the higher open probability GluN2A-subunit-containing receptors.
For the majority of these potentia- tion positions, we propose that
alteration of gating arises from steric destabilization of contact interfaces
where close apposition of the contacting partners is necessary for efficient
channel closure. Our results therefore indicate that the NMDA receptor
S1-M1 and S2-M4 linkers are dynamic during gating and can modulate the
overall energetics of this process. Furthermore, the results conceptualize
a mechanistic, as well as a possible structural, framework for pharmacologically
targeting the linkers through noncompetitive and subunit-specific modes
(pre-MSTP publications indicated with an *)
I, Kazi R, Wollmuth LP. (2011). GluN1-specific redox effects
on the kinetic mechanism of NMDA receptor activation. Biophys J.
CL, Corrales A, Talukder I, Kazi R, Akgul G, Bowen
M, Wollmuth LP. (2011). Interaction of the M4 segment with other transmembrane
segments is required for surface expression of mammalian a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) receptors. J Biol Chem. 286(46):40205-18. Epub
2011 Sep 19. PMID:21930708.
I, Wollmuth LP. (2011). Local constraints in either the GluN1
or GluN2 subunit equally impair NMDA receptor pore opening. J Gen
Physiol. 138(2):179-94. PMID:21746848.