Kathryn M. Partin, PhD
Research Interests -- Glutamate Receptor Desensitization and its Modulation by Cognition-Enhancing Drugs
As the primary mediator of fast excitatory transmission at neuronal synapses, glutamate receptors play a critical role in cognition. Dysfunction of these channels after stroke, seizure or brain injury can lead to serious patho-physiological changes that impair cognition. Glutamate receptors, and in particular the AMPA receptor family, are unique among ligand-gated ion channels in that they desensitize very rapidly, allowing the channel to close despite the fact that glutamate is still bound to its receptor. We study how the property of rapid desensitization can be exploited to develop drugs that block desensitization, and as a consequence are cognition-enhancing and potentially therapeutic after traumatic brain insult.
One goal of my laboratory is to study the mechanistic relationship between agonist-binding and subsequent gating of the channel. These studies apply a multidisciplinary approach that includes molecular biological, biophysical and electrophysiological techniques to map and characterize extracellular domains of glutamate receptors that participate in receptor desensitization and deactivation. These types of experiments contribute to our broader understanding of how ligand-gated ion channels function, as well as providing information about the molecular mechanisms of allosteric modulation of glutamate receptors by cognition-enhancing drugs.
We are also interested in how AMPA receptor expression changes in the rat cortex and hippocampus following a global ischemic insult, in an animal model of stroke that was developed here at CSU by Dr. Phil Williams and Dr. Ed Dudek. We use RT-PCR to measure changes in AMPA receptor expression after a lesion is induced. We correlate the molecular changes with functional changes that we measure with electrophysiology on acutely dissociated neurons from control versus lesioned animals. These experiments will ultimately allow us to determine how specific cognition-enhancing drugs can be targeted to specific brain regions that may have suffered injury after a stroke.
A third goal is to understand the role of glutamate receptor activity in regulating pulsatile bursting of neuroendocrine cells that secrete gonadotropin releasing hormone (GnRH), the final common pathway for the control of reproduction. We have studied the firing patterns of isolated neurons that express GFP under the GnRH promoter. We have demonstrated that these neurons express both AMPA and NMDA receptors, and that perfusion of glutamate increases the firing of isolated GnRH neurons.
Partin KM. 2001. Domain interactions regulating AMPA receptor desensitization. J Neurosci 21:1939-1948.
Kuehl-Kovarik MC, Pouliot WA, Halterman GL, Handa RJ, Dudek FE, Partin KM 2002. Episodic bursting activity and response to excitatory amino acids in acutely dissociated gonadotropin-releasing hormone neurons genetically targeted with green fluorescent protein. J Neurosci 22:2313-2322.
Leever JD, Clark S, Weeks AM, Partin KM. 2003. Identification of a site in GluR1 and GluR2 important for modulation of deactivation and desensitization. Molec Pharmacol 64:5-10.
Kuehl-Kovarik MC, Partin KM, Magnusson KR. 2003. Analysis of NMDA responses from acutely dissociated cortical neurons during aging. J Neurosci Meth 129:11-17.
Kuehl-Kovarik MC, Partin KM, Handa RJ, Dudek FE. 2005. Spike-dependent depolarizing afterpotentials contribute to endogenous bursting in gonadotropin releasing hormone neurons. Neuroscience 134:295-300.
Jin R, Clark S, Weeks AM, Dudman J, Gouaux E, Partin KM. 2005. Molecular mechanism of positive allosteric modulators acting on AMPA receptor. J Neurosci 25:9027-9036.