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Identification and characterization of new functional truncated variants of somatostatin receptor subtype 5 in
Jose Córdoba-Chacón1, Manuel D Gahete, Mario Duran-Prado
1Department of Cell Biology, Physiology and Immunology, University of Córdoba, Edificio Severo Ochoa. Planta 3. Campus de Rabanales, 14014 Córdoba, Spain.
Abstract:
Somatostatin and cortistatin exert multiple biological actions through five receptors (sst1-5); however, not all their effects can be explained by activation of sst1-5. Indeed, we recently identified novel truncated but functional human sst5-variants, present in normal and tumoral tissues. In this study, we identified and characterized three novel truncated sst5 variants in mice and one in rats displaying different numbers of transmembrane-domains [TMD; sst5TMD4, sst5TMD2, sst5TMD1 (mouse-variants) and sst5TMD1 (rat-variant)]. These sst5 variants: (1) are functional to mediate ligand-selective-induced variations in [Ca(2+)]i and cAMP despite being truncated; (2) display preferential intracellular distribution; (3) mostly share full-length sst5 tissue distribution, but exhibit unique differences; (4) are differentially regulated by changes in hormonal/metabolic environment in a tissue- (e.g., central vs. systemic) and ligand-dependent manner. Altogether, our results demonstrate the existence of new truncated sst5-variants with unique ligand-selective signaling properties, which could contribute to further understanding the complex, distinct pathophysiological roles of somatostatin and cortistatin.
Insights
Novel truncated somatostatin receptor 5 (sst5) variants were identified in rodents. These functional variants exhibit unique signaling and distribution, expanding understanding of somatostatin and cortistatin actions.
Area of Science:
- Endocrinology and Pharmacology
- Molecular and Cellular Biology
- Neuroscience
Background:
- Somatostatin and cortistatin mediate diverse biological effects via five somatostatin receptors (sst1-5).
- Existing knowledge does not fully explain all somatostatin and cortistatin actions solely through sst1-5 activation.
- Previous research identified functional truncated human sst5 variants in normal and tumoral tissues.
Purpose of the Study:
- To identify and characterize novel truncated sst5 variants in mice and rats.
- To investigate the functionality, distribution, and regulation of these novel sst5 variants.
- To explore the potential contribution of these variants to the complex roles of somatostatin and cortistatin.
Main Methods:
- Identification and characterization of truncated sst5 variants in mouse and rat models.
- Assessment of ligand-selective signaling, including intracellular calcium ([Ca(2+)]i) and cyclic AMP (cAMP) variations.
- Analysis of preferential intracellular distribution and tissue distribution patterns.
- Evaluation of differential regulation by hormonal/metabolic environmental changes.
Main Results:
- Three novel truncated sst5 variants (sst5TMD4, sst5TMD2, sst5TMD1) were identified in mice, and one (sst5TMD1) in rats, with varying transmembrane domains (TMD).
- These variants are functional, mediating ligand-selective [Ca(2+)]i and cAMP changes despite truncation.
- The variants exhibit preferential intracellular localization and largely overlap with full-length sst5 tissue distribution, but with distinct differences.
- Differential regulation by hormonal/metabolic factors was observed in a tissue- and ligand-dependent manner.
Conclusions:
- The study demonstrates the existence of novel truncated sst5 variants in rodents with distinct signaling capabilities.
- These variants possess unique ligand-selective signaling properties.
- The findings suggest that these truncated sst5 variants play a role in the complex pathophysiological actions of somatostatin and cortistatin.
