Pharmacological characterisation of native somatostatin receptors in AtT‐20 mouse tumour corticotrophs

Abstract

1 The mouse corticotroph tumour cell line AtT-20 is a useful model to investigate the physiological role of native somatostatin (SRIF, Somatotropin release inhibitory factor) receptor subtypes (sst 1 -sst 5 ). The objective of this study was to characterise the pharmacological features and the functional effects of SRIF receptors expressed by 4 SRIF analogues inhibited the forskolin-stimulated cAMP levels depending on concentration. sst 2/5 receptor-selective ligands were highly potent, whereas sst 1/3/4 receptor-selective ligands had no significant effects. The sst 2 receptor antagonist D-Tyr 8 -CYN 154806 competitively antagonised the effects of SRIF-14 and sst 2 receptor-preferring agonists, but not those of L-817,818. 5 The complex binding properties of SRIF receptor analogues indicate that sst 2 and sst 5 receptors are the predominant SRIF receptors expressed on AtT-20 cell membranes with no or only negligible presence of sst 1 , sst 3 and sst 4 receptors. In the functional studies using cAMP accumulation, only sst 2 and sst 5 receptors appear to play a role. However, the 'predominant' receptor appears to be the sst 2 receptor, although sst 5 receptors can also mediate the effect, when the ligand is not able to activate sst 2 receptors. This clearly adds flexibility to SRIF-mediated functional effects and suggests that the physiological role of SRIF and its analogues may be mediated preferentially via one subtype over another.

Expression, pharmacology, and functional role of somatostatin receptor subtypes 1 and 2 in human macrophages

“…Among synthetic ligands, we used the peptidyl multiligand analog SOM230, which binds with high affinity to sst 1,2,3,5 [42][43][44], and the peptidyl multiligand analog KE108, which binds with high affinity to all five SRIF receptors [44,45]. The sst 1 -selective peptidyl agonist CH-275 [35,41,46,47], the sst 2 -preferring peptiydyl agonist SMS 201-995 (also known as sandostatin or octreotide) [38,41,46,48,49], and the sst 2 -selective nonpeptidyl agonist L-779,976 [46, 49 -51] were also used in the absence or presence of the sst 1 -selective nonpeptydil antagonist SRA-880 [46,52,53] and the sst 2 -selective peptydil antagonist CYN [36,38,48,49,54]. All compounds were applied at 1 M, which from previous studies, is a concentration giving maximal re- ceptor occupancy [2,41].…”

Role of Amphiphysin II in Somatostatin Receptor Trafficking in Neuroendocrine Cells

“…Indeed, the residual cell surface binding of SRIF could reflect either incomplete blockade of membrane targeting of all SRIF receptor subtypes or selective sparing of the targeting of the other SRIF receptor subtypes (sst 1 , sst 2b , and sst 4 ) expressed in these cells (48,49,61). The latter possibility appears unlikely, however, because sst 2A and sst 5 receptors are the predominant SRIF receptors expressed by AtT-20 cells (92). Furthermore, the sst 1 and sst 4 subtypes have both a lower affinity than sst 2A and sst 5 subtypes for [D-Trp 8 ]SRIF, so that there should have been differences between WT and transfected cells, had these receptors been selectively involved (for review, see Refs.…”

Somatostatin and somatostatin receptors in Cushing's disease

“…IC 50 values of inhibition suggested a sst 5 -like response of ACTHinhibition. Both sst 2 and sst 5 are involved in the inhibition of ACTH release and cAMP production in AtT20 cells [56] and a functional superiority of sst 5 over sst 2 has been suggested by others as well [57,58]. On the other hand, sst 2 receptors, albeit at low level, are co-expressed with sst 5 receptors in corticotroph adenomas as well.…”