title: Truncated variants of pig somatostatin receptor subtype 5 (sst5) act as dominant-negative modulators for sst2-mediated signaling.
abstract: Somatostatin (SST) and its related peptide cortistatin (CORT) exert their multiple actions through binding to the SST receptor (sst) family, generally considered to comprise five G protein-coupled receptors with seven transmembrane domains (TMD), named sst1-sst5, plus a splice sst2B variant. However, we recently discovered that human and rodent sst5 gene expression also generates, through noncanonical alternative splicing, novel truncated albeit functional sst5 variants with less than seven TMD. Here, we cloned and characterized for the first time the porcine wild-type sst5 (psst5, full-length) and identified two novel truncated psst5 variants with six and three TMD, thus termed psst5TMD6 and psst5TMD3, respectively. In line with that observed in human and rodent truncated sst5 variants, psst5TMD6 and psst5TMD3 are functional (e.g., activate calcium signaling), selectively respond to SST and CORT, respectively, and exhibit specific tissue expression profiles that differ from full-length psst5 and often overlaps with psst2 expression. Moreover, fluorescence resonance energy transfer analysis shows that psst5 truncated variants physically interact with psst2, thereby altering their localization at the plasma membrane and specifically disrupting the cellular response to SST and/or CORT. These results represent the first characterization of a key porcine SST receptor, psst5, and, together with our previous results, provide strong evidence that alternative splicing-derived, truncated sst5 variants with distinct functional capacities exist in the mammalian lineage, where they can act as dominant-negative receptors, by interacting directly with long, seven TMD variants, potentially contributing to modulate normal and pathological SST and CORT signaling.
authors.affiliation: Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Reina Sofía University Hospital, Instituto Maimónides de Investigación Biomédica de Córdoba, and CIBER Fisiopatología de la Obesidad y Nutrición, Córdoba, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Durán-Prado
authors.forename: Manuel D
authors.initials: MD
authors.lastname: Gahete
authors.forename: Elena
authors.initials: E
authors.lastname: Delgado-Niebla
authors.forename: Antonio J
authors.initials: AJ
authors.lastname: Martínez-Fuentes
authors.forename: Rafael
authors.initials: R
authors.lastname: Vázquez-Martínez
authors.forename: Socorro
authors.initials: S
authors.lastname: García-Navarro
authors.forename: Francisco
authors.initials: F
authors.lastname: Gracia-Navarro
authors.forename: María M
authors.initials: MM
authors.lastname: Malagon
authors.forename: Raúl M
authors.initials: RM
authors.lastname: Luque
authors.forename: Justo P
authors.initials: JP
authors.lastname: Castaño
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D016466:CHO Cells; D020013:Calcium Signaling / Q000502:physiology*; D003001:Cloning, Molecular; D006224:Cricetinae; D006801:Humans; D010446:Peptide Fragments; D015202:Protein Engineering; D020033:Protein Isoforms / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology*; D017481:Receptors, Somatostatin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013552:Swine; D014018:Tissue Distribution
chemical_list: D010446:Peptide Fragments; D020033:Protein Isoforms; D017481:Receptors, Somatostatin; C106140:somatostatin receptor sst2A; C094573:somatostatin receptor 5