Inhibitory neurons shape signaling in the dorsal horn by helping to regulate responses to external stimuli. Glycine and γ-aminobutyric acid (GABA), two inhibitory neurotransmitters, are released from presynaptic vesicles. GABA binds to postsynaptic GABA receptors of the A subtype (GABAA) to mediate inhibition of signals. However, GABA also binds to GABAB receptors on the presynaptic membrane, which, in a process involving negative feedback, leads to the inhibition of GABA release from the presynaptic membrane. Kainate receptors (KARs), which make up one class of receptors that bind the excitatory neurotransmitter glutamate, can regulate the activity of excitatory and inhibitory signaling, as measured by changes in miniature inhibitory postsynaptic currents (mIPSCs). Now, Kerchner et al. show that activation of presynaptic KARs increases the frequency of mIPSCs and decreases the release of GABA and glycine from the presynaptic membrane. This KAR-dependent process required the entry of Na+, most likely through the KAR, the opening of voltage-gated Ca2+ channels on the presynaptic membrane, and vesicle fusion. In cultured neurons, prolonged kainate treatment first resulted in KAR activation-dependent GABA and glycine release, followed by kainate-dependent suppression of inhibitory signaling through the activation of autoregulatory GABAB receptors on the presynaptic membrane. Importantly, synaptically released glutamate activated KARs and promoted the GABAB-dependent suppression of the GABA and glycine inhibitory signaling. Because GABA and glycine signaling are important in inhibiting the perception of noxious stimuli (and pain), it is possible that further research into KAR antagonists might yield beneficial drugs for pain relief. MacDermott provides an excellent Preview of the article.
G. A. Kerchner, G.-D. Wang, C.-S. Qiu, J. E. Huettner, M. Zhuo, Direct presynaptic regulation of GABA/Glycine release by kainate receptors in the dorsal horn: An ionotropic mechanism. Neuron 32, 477-488 (2001). [Online Journal]
A. B. MacDermott, Glutamate and GABA: A painful combination. Neuron 32, 376-378 (2001). [Online Journal]