Iehab N. Talukder
B.S. Stony Brook University, 2005
Ph.D. Neuroscience, 2011

4th Year Medical Student

Advisor: Lonnie Wollmuth, Ph.D.

Department: Neurobiology & Behavior

Graduate Program: Neuroscience

Title: Specific Sites within the Ligand-Binding Domain and Ion Channel Linkers Modulate NMDA Receptor Gating

Abstract:

Iehab Talukder, 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

          Gating 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 of action.

Publications:
(pre-MSTP publications indicated with an *)

Talukder I, Kazi R, Wollmuth LP. (2011). GluN1-specific redox effects on the kinetic mechanism of NMDA receptor activation. Biophys J. 101(10):2389-98. PMID:22098737.

Salussolia 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.

Talukder 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.