A new type of glutamate receptor linked to inositol phospholipid metabolism

Abstract

Receptors for excitatory amino acids in the mammalian central nervous system are classified into three major subtypes^1,2, 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 directly^3–5 (ionotropic type⁶). Recently it was reported that exposure of mammalian brain cells to glutamate (Glu) or its analogues causes enhanced hydrolysis of inositol phospholipids^7,8, 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 activation^9,10, 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 (G_i or G_o^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.