Biophysics, pharmacology, and regulation of glutamate receptors.
Ion channels are fundamental to the movement and processing of information in all nervous systems, and therefore are attractive research subjects for neuroscientists. Ion channels are a fascinating research topic for additional reasons: they are beautifully evolved multifunctional machines that are both challenging and great fun to study. Professor Johnson's laboratory uses biophysical, electrophysiological, molecular, optical, pharmacological, and computational approaches to study the function, structure, and regulation of ion channels. We focus on channels involved in synaptic communication within the vertebrate nervous system.
Of particular interest to the laboratory are N-methyl-D-aspartate (NMDA) receptors, ligand-gated channels that are members of the glutamate receptor family of ion channels. Glutamate receptors mediate most of the fast excitatory synaptic transmission in vertebrate nervous systems. NMDA receptors are unusual receptors in many respects. Their unique combination of characteristics permit them to play pivotal roles in basic nervous system functions, including brain development and learning and memory. NMDA receptors are also involved in many nervous system disorders, including epilepsy, schizophrenia, ischemia, Alzheimer’s disease, and Huntington’s disease.
We use whole-cell and single-channel patch clamp recordings of glutamate receptors in transfected cell lines, cultured neurons, and brain slices. Our ability to integrate measurements of cellular and single-channel activity mediated by native, wild-type recombinant, and mutant receptors with quantitative modeling at multiple levels affords broad insight into how receptors function. Our research addresses a wide range of topics, including basic aspects of receptor function (e.g., channel permeation, block, voltage dependence, and gating), the mechanism of action of therapeutic drugs, and the roles of NMDA receptors in activation of inhibitory interneurons.
Recent work in our laboratory suggested that specific subtypes of NMDA receptors serve as important targets in the treatment of Alzheimer’s disease. We plan to use behavioral studies in genetically modified mice, in addition to many of the approaches mentioned above, to test this hypothesis.
Gielen, M., Retchless, B.S., Mony, L., Johnson, J.W., and Paoletti, P. Mechanism of differential control of NMDA receptor activity by NR2 subunits. Nature 459,703-707, 2009.
Kotermanski, S.E., and Johnson, J.W. Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer’s drug memantine. J. Neurosci. 29, 2774-2770, 2009.
Clarke, R.J., and Johnson, J.W. Voltage-dependent gating of NR1/2B NMDA receptors. J. Physiol. 586, 5727-5741, 2008.
Gielen, M., Le Goff, A., Stroebel, D., Johnson, J.W., Neyton, J., and Paoletti, P. Structural rearrangements of NR1/NR2A NMDA receptors during allosteric inhibition. Neuron 57, 80-93, 2008.
Qian, A., and Johnson, J.W. Permeant ion effects on external Mg2+ block of NR1/2D NMDA receptors. J. Neurosci. 26, 10899-10910, 2006.