Evidence for a glutamate receptor of the AMPA subtype which mediates insulin release from rat perfused pancreas

Abstract

1 The effect of l-glutamate has been studied on insulin secretion by the isolated perfused pancreas of the rat. The glutamate receptor subtype involved has been characterized. 2 In the presence of a slightly stimulating glucose concentration (8.3 mm), l-glutamate (5 × 10⁻⁵−4 × 10⁻³ m) induced an immediate, transient and concentration-dependent insulin response. On the other hand, in the presence of a non stimulating glucose concentration (2.8 mm), l-glutamate (10⁻³ m) did not modify the basal insulin secretion. 3 The three non-NMDA receptor agonists, kainate (10⁻⁴−10⁻³ m), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA, 5 × 10⁻⁵−10⁻⁴ m) and quisqualate (5 × 10⁻⁶−5 × 10⁻⁵ m) all provoked a transient and concentration-dependent insulin response from pancreas perfused with 8.3 mm glucose. Compared with glutamate, kainate exhibited a similar efficacy, whereas AMPA and quisqualate elicited only a 3 fold lower maximal insulin response. In contrast, NMDA (10⁻⁴−10⁻³ m) was ineffective. 4 An antagonist of non-NMDA receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 5 × 10⁻⁵ m) totally prevented the stimulatory effect of l-glutamate (4 × 10⁻⁴ m) and kainate (2 × 10⁻⁴ m). In contrast, the NMDA receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ((+) MK801) was without effect. 5 The insulin secretory effect of glutamate (4 × 10⁻⁴ m) was not affected by atropine (3 × 10⁻⁷ m) or tetrodotoxin (3 × 10⁻⁶ m). 6 Quisqualate at a high maximally effective concentration (4 × 10⁻⁴ m) inhibited glutamate (10⁻³ m) or kainate (4 × 10⁻⁴ m)-induced insulin release. 7 This study shows that l-glutamate stimulates insulin secretion in rat pancreas, by acting on an excitatory amino acid receptor of the AMPA subtype.