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NEUROPHARMACOLOGY

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

Pharmacology and Toxicology Section, Department of Experimental Medicine (A.P., M.F., F.L., M.R.), Center of Excellence for Biomedical Research (A.P., M.R.), and Department of Endocrinological and Metabolic Sciences (M.A.), University of Genoa, Genoa, Italy

Somatostatin receptors and glutamate N-methyl-D-aspartate (NMDA) receptors coexist on 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 pharmacologically characterized as sst5 type in experiments in Mg²⁺-free solutions. Here, 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 membranes. We then investigated 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 was partly prevented by the protein kinase C inhibitor GF109203X [dihydrochloride3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione] and by the nonreceptor tyrosine kinase (Src) inhibitors PP2 [3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-D]pyrimidin-4-amine] and lavendustin A; it was largely and almost totally abolished by the phospholipase C inhibitor U73122 [1-(6-[([17]-3-methoxyextra-1,3,5[10]-trien-17-yl)amino]hexyl)-1H-pyrrole-2,5-dione] and by the Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN93 [N-(2-[N-[4-chlorocinnamyl]-N-methyl-amino-methyl]phenyl)-N-(2-hydroxyethyl)-4-methoxy-benzene-sulfonamide-phosphate salt], respectively; and it was unaffected by the protein kinase A inhibitor H89 [N-(2-[p-bromocinnamylamino]ethyl)5-isoquinolinesulfonamide hydrochloride]. The norepinephrine release evoked by somatostatin-14/NMDA/glycine was inhibited when anti-phosphotyrosine antibodies had been entrapped into synaptosomes. Entrapping the recombinant activated tyrosine kinase pp60^c-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 up-regulation of the ongoing NMDA receptor activity.

Address correspondence to: Dr. Anna Pittaluga, Dipartimento di Medicina Sperimentale, Sezione Farmacologia e Tossicologia, Viale Cembrano 4, 16148 Genova, Italy. E-mail: pittalug{at}pharmatox.unige.it

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