FUNCTIONAL SIMILARITIES AND DIFFERENCES OF AMPA AND KAINATE RECEPTORS EXPRESSED BY CULTURED RAT SENSORY NEURONS C. J. LEE, C. LABRAKAKIS, D. J. JOSEPH AND A. B. MACDERMOTT* Department of Physiology and Cellular Biophysics and the Center for Neurobiology and Behavior, Columbia University, 630 West 168 th Street BB1106, New York, NY 10032, USA Abstract—Dorsal root ganglion neurons express functional AMPA and kainate receptors near their central terminals. Activation of these receptors causes a decrease in gluta- mate release during action potential evoked synaptic transmission. Due to differences in kinetic properties and expression patterns of these two families of glutamate receptors in subpopulations of sensory neurons, AMPA and kainate receptors are expected to function differently. We used embryonic dorsal root ganglion (DRG) neurons maintained in culture to compare functional properties of kainate and AMPA receptors. Most DRG neurons in culture expressed kainate receptors and about half also expressed AMPA receptors. Most AMPA and kainate receptor-ex- pressing DRG neurons were sensitive to capsaicin, sug- gesting involvement of these glutamate receptors in noci- ception. When activated by kainate, AMPA receptors were capable of driving a sustained train of action potentials while kainate receptors tended to activate action potential firing more transiently. Glutamate elicited more action po- tentials and a larger steady-state depolarization in neurons expressing both AMPA and kainate receptors than in neu- rons expressing only kainate receptors. Adding to their more potent activation properties, AMPA receptors recov- ered from desensitization much more quickly than kainate receptors. Activation of presynaptic receptors by low con- centrations of kainate, but not ATPA, caused a tetrodotox- in-sensitive increase in the frequency of spontaneous EP- SCs recorded in dorsal horn neurons. By recording synap- tic pairs of DRG and dorsal horn neurons, we found that activation of presynaptic kainate and AMPA receptors de- creased evoked glutamate release from terminals of DRG neurons in culture. Our data suggest that the endogenous ligand, glutamate, will cause a different physiological im- pact when activating these two types of non-NMDA gluta- mate receptors at central or peripheral nerve endings of sensory neurons. © 2004 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: dorsal root ganglion, action potential, presynap- tic receptors, synaptic transmission, spontaneous EPSCs, capsaicin. Nociceptors are a heterogeneous group of sensory neu- rons that sense noxious, damage-causing stimuli in the periphery and transmit those signals to the CNS. They extend their processes peripherally and centrally from cell bodies that are located in the dorsal root ganglion (DRG). Nociceptive fibers innervate peripheral tissues such as skin and visceral organs and detect noxious thermal, chemical and mechanical stimuli. Centrally, fi- bers from these nociceptors enter the spinal cord through the dorsal root entry-zone and form synapses with dorsal horn neurons located in the superficial lam- ina of the spinal cord. Nociceptors release glutamate from their central ter- minals. The glutamate activates postsynaptic ionotropic glutamate receptors for rapid excitatory communication with target dorsal horn neurons (Schneider and Perl, 1988; Yoshimura and Jessell, 1990). All three classes of ionotropic glutamate receptors, NMDA, AMPA, and kai- nate receptors, are expressed by dorsal horn neurons and mediate fast synaptic transmission at postsynaptic sites (Yoshimura and Jessell, 1990; Li et al., 1999). Accumulating evidence demonstrates that not only spinal cord dorsal horn neurons but also peripheral sen- sory DRG neurons express ionotropic glutamate recep- tors. Functional kainate receptors are expressed by acutely dissociated, small diameter, DRG neurons (Huettner, 1990) in a defined population of IB4 positive nociceptors (Lee et al., 2001). Functional AMPA recep- tors are preferentially expressed near the presynaptic terminals of a subpopulation of peripherin positive noci- ceptors (Lee et al., 2002). Activation of presynaptic AMPA and kainate receptors causes a decrease in evoked release of glutamate from central terminals of nociceptors (Lee et al., 2002; Kerchner et al., 2001). Glutamate receptors also have been proposed to be transducers at the peripheral endings of nociceptors (Carlton et al., 1995; Jackson et al., 1995). Kainate and glutamate applied to exposed skin was shown to cause spinal reflexes in rat spinal cord-tail preparation (Ault and Hildebrand, 1993) and ultrastructural studies showed that AMPA and kainate receptor subunits are expressed in the peripheral axons of small diameter fibers in the rat and human skin (Coggeshall and Carl- ton, 1998; Kinkelin et al., 2000). Because AMPA and kainate receptors display a dis- tinct distribution and expression pattern (Lu et al., 2002; Chambille and Rampin, 2002; Lee et al., 2001, 2002), it is predicted that they would be engaged in different *Corresponding author. Tel: 1-212-305-3889; fax: 1-212-305-3723. E-mail address: abm1@columbia.edu (A. B. MacDermott). Abbreviations: AMPA, alpha-amino-3-hydroxy-5-methyl-4-isox- azolepropionic acid; ConA, concanavalin A; CTZ, cyclothiazide; DRG, dorsal root ganglion; EPSCs, excitatory postsynaptic currents; NGF, nerve growth factor; SEM, standard error of mean; sEPSCs, sponta- neous EPSCs; TTX, tetrodotoxin. Neuroscience 129 (2004) 35– 48 0306-4522/04$30.000.00 © 2004 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2004.07.015 35