title: Binding and functional properties of the novel somatostatin analogue KE 108 at native mouse somatostatin receptors.
abstract: Clinically used somatostatin (SRIF) analogs, octreotide and lanreotide, act primarily by binding to SRIF receptor subtype 2 (sst2). In contrast, the recently described multiligand SOM230 binds with high affinity to sst(1-3) and sst5 and KE 108 is characterised as a high affinity ligand for all five SRIF receptors. In tumoural mouse corticotrophs (AtT-20 cells) and in mouse hippocampus, binding and functional features of KE 108 were examined and compared to SRIF-14, octreotide and SOM230. In AtT-20 cells, KE 108 bound with high affinity at [125I]LTT-SRIF-28-labelled sites similarly to SRIF-14, octreotide and SOM230. At the functional level, all four ligands increased guanosine-5'-O-(3-[35S]thio)-triphosphate binding and decreased cAMP accumulation or intracellular Ca2+ concentration through G(i/o) proteins. In hippocampal slices, KE 108, octreotide and SOM230 also bound with high affinity at [125I]LTT-SRIF-28-labelled sites similarly to SRIF-14, but KE 108, octreotide or SOM230 did not influence spontaneous epileptiform activity which was, in contrast, inhibited by SRIF-14. In conclusion, this study demonstrates that KE 108 has high affinity for native mouse SRIF receptors. Functionally, KE 108 mediates SRIF action at sst(2/5) in corticotrophs whereas it does not mimic the SRIF-induced inhibition of hippocampal excitation suggesting that the high potency and efficacy of a synthetic ligand to all known SRIF receptors may not reproduce entirely the effects of the natural SRIF.
authors.affiliation: Dipartimento di Fisiologia e Biochimica G. Moruzzi, Università di Pisa, 56127 Pisa, Italy. d.cervia@dfb.unipi.it
authors.forename: Davide
authors.initials: D
authors.lastname: Cervia
authors.forename: Daniel
authors.initials: D
authors.lastname: Langenegger
authors.forename: Edi
authors.initials: E
authors.lastname: Schuepbach
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cammalleri
authors.forename: Philippe
authors.initials: P
authors.lastname: Schoeffter
authors.forename: Herbert A
authors.initials: HA
authors.lastname: Schmid
authors.forename: Paola
authors.initials: P
authors.lastname: Bagnoli
authors.forename: Daniel
authors.initials: D
authors.lastname: Hoyer
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D016257:Fura-2 / Q000031:analogs & derivatives* / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011869:Radioligand Assay / Q000379:methods; D017481:Receptors, Somatostatin / Q000187:drug effects*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors*; D013460:Sulfur Isotopes / Q000494:pharmacology; D013997:Time Factors
chemical_list: D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; D013460:Sulfur Isotopes; C473958:Tyr(0)-(cyclo-D-Dab-Arg-Phe-Phe-D-Trp-Lys-Thr-Phe); C049925:fura-2-am; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013004:Somatostatin; D000242:Cyclic AMP; D002118:Calcium; D016257:Fura-2