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.
|Autori:||Cervia, D; Langenegger, D; Schuepbach, E; Cammalleri, Maurizio; Schoeffter, P; SCHMID H., A; Bagnoli, Paola; Hoyer, D.|
|Titolo:||Binding and functional properties of the novel somatostatin analogue KE 108 at native mouse somatostatin receptors|
|Anno del prodotto:||2005|
|Appare nelle tipologie:||1.1 Articolo in rivista|