Lonnie P. Wollmuth

Molecular Properties of Cortical Signaling

Lonnie P. Wollmuth
Assistant Professor
PhD, University of Washington

Claudia Jatzke, Postdoctoral Fellow
Alexander Sobolevsky, Postdoctoral Fellow
LeeAnn Rooney, Research Technician
Junryo Watanabe, Graduate Student

The flow of information in the brain is controlled by specialized structures called synapses. These structures determine how cells communicate with each other, and alterations in their properties are widely believed to underlie changes in brain function including those associated with learning and memory and numerous disease states. Research in my laboratory concerns understanding the mechanism by which synapses contribute to signaling in the brain. Since we want to understand the details of synaptic function, our approach is molecular and cellular in orientation and highly quantitative.

Excitatory neurotransmission in the brain is predominantly mediated by glutamate receptors (GluRs). These receptors, notably N-methyl-D-aspartate (NMDAR), -amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPAR) and kainate subtypes, display a variety of molecular and biophysical properties that contribute to their versatility and prominence in cell signaling. Perhaps most significant is that the open channel represents a pathway for Ca2+ entry. Indeed, Ca2+ flux through these channels mediates many of the biological functions of their activation including their proposed roles in changes in synaptic efficacy, in development of cellular connections and—when excessive—in cell death. The major focus of my laboratory is to define the molecular basis by which these receptors allow Ca2+ into the cell and how this Ca2+, once inside, modulates synaptic function. To address these issues and to gain mechanistic insights, we take advantage of a variety of techniques including patch clamp and optical methods to study glutamate-mediated currents and Ca2+ influx, we study these processes in both recombinant and native channels and compliment this work with molecular biology techniques including site-directed mutagenesis and gene-targeted mice. The goal of this work is to elucidate how synaptically controlled Ca2+ influx via GluR channels is regulated at a molecular and cellular level and how it contributes quantitatively to synaptic function especially during behavior and pathophysiology.

Selected publications:

Beck, C., Wollmuth, L. P., Seeburg, P. H., Sakmann, B. & Kuner, T. (1999). NMDAR channel segments forming the extracellular vestibule inferred from the accessibility of substituted cysteines. Neuron 22: 559-570.

Wollmuth, L. P. & Sakmann, B. (1998). Different mechanisms of Ca²⁺ transport in NMDA and Ca²⁺-permeable AMPA glutamate receptor
channels. J. Gen. Physiol. 112: 623-636.

Wollmuth, L. P., Kuner, T. & Sakmann, B. (1998a). Adjacent asparagines in the NR2-subunit of the NMDA receptor channel control the
voltage dependent block by extracellular Mg²⁺. J. Physiol. (Lond.) 506: 13-32.

Wollmuth, L. P., Kuner, T. & Sakmann, B. (1998). Intracellular Mg²⁺ interacts with structural determinants of the narrow constriction
contributed by the NR1-subunit in the NMDA receptor channel. J. Physiol. (Lond.) 506: 33-52.

Kuner, T., Wollmuth, L. P., Karlin, A., Seeburg, P. H. & Sakmann, B. (1996). Structure of the NMDA receptor channel M2 segment
inferred from the accessibility of substituted cysteines. Neuron 17: 343-352.

Wollmuth, L. P., Kuner, T., Seeburg, P. H. & Sakmann, B. (1996). Differential contribution of the NR1- and NR2A-subunits to the
selectivity filter of recombinant NMDA receptor channels. J. Physiol. (Lond.) 491: 779-797.