A new type of glutamate receptor linked to inositol phospholipid metabolism

Receptors for excitatory amino acids in the mammalian central nervous system are classified into three major subtypes1,2, ones which prefer N-methyl-D-aspartate (NMDA), quisqualate (QA), or kainate (KA) as type agonists respectively. These receptors are considered to mediate fast postsynaptic potentials by activating ion channels directly3–5 (ionotropic type6). Recently it was reported that exposure of mammalian brain cells to glutamate (Glu) or its analogues causes enhanced hydrolysis of inositol phospholipids7,8, but it is not clear whether the enhanced hydrolysis is the cause or effect of physiological responses. Membrane depolarization or Ca2+ influx, which can result from Glu receptor activation9,10, can induce enhanced hydrolysis of inositol phospholipids11. We have characterized the functional properties of two types of excitatory amino-acid responses, those activated by QA (or Glu) and those activated by KA, induced in Xenopus oocytes injected with rat-brain messenger RNA12. We report evidence for a new type of Glu receptor, which prefers Q A as agonist, and which directly activates inositol phospholipid metabolism through interaction with GTP-binding regulatory proteins (Gi or Go 13,14), leading to the formation of inositol 1,4,5-trisphosphate (InsP3) and mobilization of intracellular Ca2+. This QA/Glu reaction is inhibited by islet-activating protein (IAP, pertussis toxin15), but was not blocked by Joro spider toxin (JSTX)16, a specific blocker of traditional ionotropic QA/Glu receptors.