Somatostatin-induced activation and up-regulation of N-methyl-D-aspartate receptor function: mediation through calmodulin-dependent protein kinase II, phospholipase C, protein kinase C, and tyrosine kinase in hippocampal noradrenergic nerve endings.

Somatostatin receptors and glutamate NMDA receptors coexist and interact in hippocampal noradrenergic axon terminals. Activation of somatostatin receptors was previously found to positively influence the function of NMDA receptors regulating norepinephrine release. The somatostatin receptors involved were pharmacologicaaly characerized as sst type, in experiments in Mg2+-free solutions.Inthe present work, we first confirm the pharmacology of these receptors using selective sst5 ligands in Mg2+-containing solutions. Moreover, we show by western blot that the sst5 protein exists on purified hippocampal synaptosomal membrames. We here investigate the pathways connecting the two receptors using as a functional response the release of norepinephrine from rat hippocampal synaptosomes in superfusion. The release of norepinephrine evoked by somatostatin-14 plus NMDA/glycine, in presence of external Mg2+ ions, was partly prevented by the protein kinase C inhibitor GF109203X and by the non-receptor tyrosine kinase (Src) inhibitors PP2 and lavendustin A; it was largely and almost totally abolished by the phospholipase C inhibitor U73122 and by the Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN93, respectively; it was unaffected by the protein kinase A inhibitor H89. The norepinephrine release evoked by somatostatin-14/NMDA/glycine was inhibited when anti-phosphotyrosine antibodies had been entrapped inside the synaptosomes. Entrapping the recombinant activated tyrosine kinase pp60c-Src strongly potentiated the release of norepinephrine elicited by NMDA/glycine in Mg2+-free medium, but failed to permit NMDA receptor activation in presence of external Mg2+ ions. The results suggest the involvement of CaMKII in the sst5 receptor-mediated activation of NMDA receptors in presence of Mg2+ and of the PLC/PKC/Src pathway in the upregulation of the ongoing NMDA receptor activity.