GluR5 Goes Both Ways

Science's STKE  12 Aug 2003:
Vol. 2003, Issue 195, pp. tw312-TW312
DOI: 10.1126/stke.2003.195.tw312

The neurotoxin kainate activates a particular class of ionophoric glutamate receptor, the kainate receptor. Kainate also inhibits neurotransmitter release through a pathway that involves a pertussis toxin-sensitive G protein (heterotrimeric guanine nucleotide-binding protein) and protein kinase C (PKC). Rozas et al. investigated the relation between these effects in cultured rat dorsal root ganglion cells (DRGs) and discovered that kainate's activation of the G protein-coupled pathway depended on expression of GluR5, an ion channel-forming subunit of the kainate receptor, but was independent of functional ion channel activity. The authors used calcium imaging to show that kainate stimulated a rise in intracellular calcium ([Ca2+]i); a fraction that was sensitive to pertussis toxin persisted in the absence of extracellular calcium, which suggests that it represented release from intracellular stores. Calcium imaging in combination with electrophysiological analysis indicated that pretreatment with kainate inhibited Ca2+ influx in response to depolarization with potassium; this was sensitive to pertussis toxin and inhibitors of PKC. There was no correlation between kainate-stimulated Ca2+ influx (a marker of ionophoric activity) and kainate inhibition of depolarization-dependent Ca2+ influx. Moreover, inhibition of depolarization-dependent Ca2+ influx occurred at kainate concentrations that were too low to affect [Ca2+]i directly and in the absence of extracellular sodium (which affects receptor gating). Both kainate-stimulated Ca2+ influx and kainate's inhibition of depolarization-dependent Ca2+ influx were abolished in DRGs from mice lacking GluR5. Pharmacological analysis suggested that kainate-dependent release of glutamate from primary sensory afferents involved a G protein-mediated pathway. Thus GluR5 appears to mediate distinct kainate signaling pathways; one involves formation of an ionophoric receptor and one involves G protein activation.

J. L. Rozas, A. V. Paternain, J. Lerma, Noncanonical signaling by ionotropic kainate receptors. Neuron 39, 543-553 (2003). [Online Journal]