Biophysics, pharmacology, regulation, and structure of glutamate receptors.
Ion channels are fundamental to the movement and processing of information in all nervous systems, and thus are critically important topics of neuroscience research. 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, molecular, optical, pharmacological, and computational approaches to study the function, structure, and regulation of ion channels. We focus on channels involved in synaptic communication.
Of particular interest to the laboratory are N-methyl-D-aspartate receptors (NMDARs), ligand-gated ion channels that are members of the glutamate receptor family. Glutamate receptors mediate most fast excitatory synaptic transmission in vertebrate nervous systems. NMDARs are unusual receptors in many respects. Their unique combination of biophysical properties permit NMDARs to play pivotal roles in basic nervous system functions, including brain development and learning and memory. NMDARs also are involved in many nervous system disorders, including schizophrenia, Alzheimer’s disease, depression, Huntington’s disease, epilepsy, and ischemia.
We integrate approaches to advance understanding of glutamate receptors at multiple levels. Central to our research are patch-clamp electrophysiological recording techniques. To gain basic insight into receptor function we combine whole-cell and single-channel recordings from wild-type and mutant receptors with powerful computational approaches including kinetic modeling, and structural modeling using molecular dynamics simulations (in collaboration with the lab of Dr. Maria Kurnikova, Department of Chemistry, Carnegie Mellon University). Understanding the role of NMDARs in disease is advanced through study of clinically important drugs that act on NMDARs. Examples of such drugs are the NMDAR channel blockers memantine and ketamine: memantine is one of the few drugs approved for treatment of Alzheimer’s disease, whereas ketamine has generated great interest as a fast-acting antidepressant, but also a drug that induces schizophrenia-like symptoms in humans. We are examining the mechanism of therapeutic action of memantine by integrating data from heterologously expressed recombinant receptors, brain slice recordings of specific neuronal subtypes, and behavioral study of wild-type and mutant mice.
Johnson, J.W., Glasgow, N.G. and Povysheva, N.V. Recent insights into the mode of action of memantine and ketamine. Curr. Opin. Pharmacol. 20, 54-63, 2015.
Glasgow, N.G., Siegler Retchless, B. and Johnson, J.W. Molecular bases of NMDA receptors subtype-dependent properties. J. Physiol. 593, 83-95, 2015.
Kotermanski, S.E., Johnson, J.W. and Thiels, E. Comparison of behavioral effects of the NMDA receptor channel blockers memantine and ketamine in rats. Pharmacology, Biochemistry and Behavior 109, 67-76, 2013.
Clarke, R.J., Glasgow, N.G. and Johnson, J.W. Mechanistic and structural determinants of NMDA receptor voltage-dependent gating and slow Mg2+ unblock. J. Neurosci. 33, 4140-4150, 2013.
Povysheva, N.V. and Johnson, J.W. Tonic NMDA receptor-mediated current in prefrontal cortical pyramidal cells and fast-spiking interneurons. J. Neurophysiol. 107, 2232-2243, 2012.
Siegler Retchless, B., Gao, W. and Johnson, J.W. A single GluN2 subunit residue controls NMDA receptor channel properties via intersubunit interaction. Nature Neurosci. 15, 406-413, 2012.
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.