Novel modalities of somatostatin actions

Abstract

The first part of this contribution reviews the current knowledge about endocrine and neuromodulatory actions of somatostatin. These biological actions are exerted according to endocrine, paracrine and autocrine modes of action and involve five distinct types of membrane receptors belonging to the 'super-family' of G-protein-coupled receptors. A new concept concerning a juxtacrine mode of action has recently been introduced to refer to the intervention of cytokines and growth factors in direct, cell-to-cell communication. The evidence in favor of juxtacrine actions of somatostatin will be presented in the second part of this review and illustrated by our own results on macrophage-lymphocyte T interactions in the immune system and spermatogonia -Sertoli cell interactions in mammalian testis. Another phenomenon such as ligand-induced somatostatin receptor homo-and hetero-dimerization resulting in 'poly'-receptors (with characteristics different from those of each of the two receptors forming the complex) is also at the origin of a novel mode of somatostatin action. The latter will be illustrated by the data obtained on human pituitary adenomas with somatostatin analogs specific for either 'poly'-receptor or relevant individual receptors. The arguments in favor of the analogous mode of actions among different families of chemical messengers such as peptides, cytokines and growth factors are discussed in the concluding section. The emerging unifying concepts on such functional analogies might provide a useful basis for the development of synthetic analogs not only for bioactive peptides but also for other types of chemical messengers.European Journal of Endocrinology 151 643-655

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

“…The capacity of SRIF receptors, including sst 1 and sst 2 , to regulate cell proliferation/viability negatively through indirect and direct mechanisms has been reported repeatedly in many systems [3,64]. As SOM230 and KE108 are able to activate sst 1 and sst 2 , it is unclear whether activation of one or both receptor subtypes leads to the inhibition of macrophage viability.…”

“…In different types of immune cells, the modulation of cell viability by SRIF-14 is complex and may occur through distinct receptor subtypes. For example, the observed actions of SRIF-14 on lymphocyte proliferation are multimodal: inhib-itory and stimulatory effects have been reported depending on the SRIF-14 concentration, the way in which the immune cell activation was achieved, and the cell phenotype [4,64].…”

Identification of transcriptional regulatory elements in the human somatostatin receptor sst2 promoter and regions including estrogen response element half-site for estrogen activation

“…The peptide exerts its effects by interacting with specific G protein-coupled somatostatin receptors. There exist five distinct somatostatin receptor subtypes (sst1-sst5), among which sst2 is well known to be involved in many physiological functions (Patel 1999, Reubi 2003, Krantic et al 2004, Olias et al 2004. These include inhibitory regulation of endocrine and exocrine secretions (Patel 1999), such as GH, adrenocorticotrophin, glucagon, and gastric acid (Martinez et al 1998, Ren et al 2003, Ben-Shlomo et al 2005.…”

Intercellular Communication

“…Juxtacrine mode of action (derived from juxta: nearby, Latin) is a direct and intimate contact between two cells such as macrophage-T lymphocyte, spermatogoniaSertoli cell or endothelial cell (EC) and the leukocyte (Krantic et al, 2004;Patel et al, 1993;Zimmerman et al, 1993). This signaling form provides a mechanism for strict spatial control of activation of one cell by another and juxtacrine signaling is likely to be common in physiologic events that require tight regulation (Zimmerman et al, 1993).…”

“…Activation of sst2 receptor by somatostatin binding leads to a diminished expression of stem cell factor (SCF) expression by Sertoli cells. This inhibition of SCF is associated with a decrease in spermatogonia proliferation (Krantic et al, 2004). Immunologic synapse which involve multiple adhesion and regulatory molecules between antigenpresenting cell (APC) and T-cell can also be considered juxtacrine communication (Bromley et al 2001;Biggs et al, 2011).…”