Somatostatin potentiates NMDA receptor function via activation of InsP(3) receptors and PKC leading to removal of the Mg(2+) block without depolarization.
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 [(3)H]-NA elicited by alpha-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 sst(5) subtype, but not by the new selective sst(1) - sst(4) 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 Mg(2+) 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. It is concluded that SRIF receptors, possibly of the sst(5) subtype, can exert a permissive role on NMDA receptors colocalized on hippocampal noradrenergic terminals: activation of sst(5) receptors is coupled to pertussis toxin-sensitive G proteins enhancing phosphoinositide metabolism with activation of InsP(3) receptors and PKC; NMDA receptor subunits might be phosphorylated with consequent removal of the Mg(2+) block in absence of depolarization.
Pittaluga
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Dipartimento di Medicina Sperimentale, Sezione di Farmacologia e Tossicologia, Università di Genova, Viale Cembrano 4, 16148 Genova, Italy.
Bonfanti
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Raiteri
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D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D004594:Electrophysiology; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006727:Hormone Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008274:Magnesium / Q000502:physiology*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D009411:Nerve Endings / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*; D013004:Somatostatin / Q000494:pharmacology*; D013564:Sympathetic Nervous System / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D015220:Calcium Channels; D020536:Enzyme Activators; D006727:Hormone Antagonists; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010455:Peptides; D018160:Receptors, Cytoplasmic and Nuclear; D016194:Receptors, N-Methyl-D-Aspartate; D013004:Somatostatin; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D008274:Magnesium