Somatostatin potentiates NMDA receptor function via activation of InsP3 receptors and PKC leading to removal of the Mg2+ block without depolarization

摘要

class="enumerated" style="list-style-type:decimal">N-methyl-D-aspartate (NMDA) receptors exist on noradrenergic axon terminals and mediate enhancement of noradrenaline (NA) release. We here investigated modulation by somatostatin (SRIF, somatotropin release inhibiting factor) of the NMDA-induced release of NA using superfused hippocampal synaptosomes.The NMDA response was increased by SRIF-28 and SRIF-14, but not SRIF-28(1–14), whereas the release of [³H]-NA elicited by α-amino-3-hydroxy-5-methylisoxazide-4-propionic acid (AMPA) was unaffected. SRIF-14 did not mimic glycine at the NMDA receptor but activated SRIF receptors sited on noradrenergic terminals.The SRIF-14 effect was blocked by pertussis toxin but mimicked by mastoparan, 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 sst5 subtype, but not by the new selective sst1–sst4 receptor agonists L797591, L779976, L796778 and L803087.Protein kinase C (PKC) inhibitors (H7, staurosporine, GF 209103X, cheleritrine and sphingosine) prevented the SRIF-14 effect, while phorbol 12-myristate 13-acetate enhanced the NMDA response.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 (InsP3) receptors with heparin abolished the effect of SRIF-14.It is concluded that SRIF receptors, possibly of the sst5 subtype, can exert a permissive role on NMDA receptors colocalized on hippocampal noradrenergic terminals: activation of sst5 receptors is coupled to pertussis toxin-sensitive G proteins enhancing phosphoinositide metabolism with activation of InsP3 receptors and PKC; NMDA receptor subunits might be phosphorylated with consequent removal of the Mg²⁺ block in absence of depolarization.