Department of Neurobiology, University of Utah, USA
Protein regulation of NMDAR-mediated signaling
Many animals locate resources by navigating along resource-associated sensory gradients. We have molecular and circuit-based insights into the neuronal control of navigation in the nematode C. elegans. The control of navigation is dependent on interneurons that express postsynaptic AMPA, kainate or NMDA receptors. These receptors have markedly different biophysical properties, which allow synaptic inputs to have differential effects on navigation. We take advantage of the links between synaptic signaling and quantifiable behaviors to screen for C. elegans mutants with disrupted glutamatergic signaling. Our genetic approach has identified proteins that modify AMPAR and NMDAR function or localization, including NRAP-1, a secreted NMDAR auxiliary protein that is required for NMDAR-mediated current and behavior. We demonstrate that NRAP-1 is sufficient to gate NMDARs and greatly enhances glutamate-mediated NMDAR gating, thus conferring coincident activation properties to the NMDAR. We suggest that the ATD is a primary determinant of NRAP-1- and glutamate-mediated gating of NMDARs. We determined the crystal structure of NRAP-1 at 1.9 Å resolution, which revealed two distinct domains positioned around a central LDLa domain. The NRAP-1 structure, combined with chimeric and mutational analyses, suggests a model where the three NRAP-1 domains work cooperatively to modify the gating of NMDARs.
Villu Maricq received his medical and scientific training at the University of California, San Francisco & the University of California, Berkeley. Following postdoctoral work at UCSF with Dr. David Julius and Dr. Cori Bargmann, Dr. Maricq joined the faculty at the University of Utah. Dr. Maricq’s research explores the molecular machinery that contributes to the information-processing capabilities of the nervous system, with a focus on neural circuits and the regulation and function of synaptic transmission. He approaches these questions relies with a genetics-based strategy, and aims to gain a mechanistic understanding of how synaptic receptors are delivered to synapses, how auxiliary proteins modulate their function, and the synaptic control of complex behaviors such as learning and memory. Dr. Maricq has received numerous awards for his research, including a NIH Director’s Pioneer award.