Somatostatin potentiates NMDA receptor function via activation of InsP(3) receptors and PKC leading to removal of the Mg2+ block without depolarization

1 N-methyl-D-aspartate (NMDA) receptors exist on noradrenergic axon termina ls and mediate enhancement of noradrenaline (NA) release. We here investiga ted modulation by somatostatin (SRIF, somatotropin release inhibiting facto r) of the NMDA-induced release of NA using superfused hippocampal synaptoso mes. 2 The NMDA response was increased by SRIF-28 and SRIF-14, but not SRIF-28(( 1-14)), whereas the release of [H-3]-NA elicited by alpha-amino-3-hydroxy-5 -methylisoxazide-4-propionic acid (AMPA) was unaffected. SRIF-14 did not mi mic glycine at the NMDA receptor but activated SRIF receptors sited on nora drenergic terminals. 3 The SRIF-14 effect was blocked by pertussis toxin but mimicked by mastopa ran, a G-protein activator. BIM-23056, but not Cyanamid 154806, antagonized the SRIF-14 effect. This effect was mimicked by L362855, a partial agonist at the sst(5) subtype, but not by the new selective sst(1)-sst(4) receptor agonists L797591, L779976, L796778 and L803087. 4 Protein kinase C (PKC) inhibitors (H7, staurosporine, GF 209103X, cheleri trine and sphingosine) prevented the SRIF-14 effect, while phorbol 12-myris tate 13-acetate enhanced the NMDA response. 5 SRIF-14 permitted NMDA receptor activation in the presence of 1.2 mM Mg2 ions, both in hippocampal synaptosomes and slices. Blockade of inositol-1, 4,5-trisphosphate (InsP(3)) receptors with heparin abolished the effect of SRIF-14. 6 It is concluded that SRIF receptors, possibly of the sst, subtype, can ex ert a permissive role on NMDA receptors colocalized on hippocampal noradren ergic terminals: activation of sst(5) receptors is coupled to pertussis tox in-sensitive G proteins enhancing phosphoinositide metabolism with activati on of InsP(3) receptors and PKC; NMDA receptor subunits might be phosphoryl ated with consequent removal of the Mg2+ block in absence of depolarization .