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Identification and Characterization of Two Novel Truncated but Functional Isoforms of the Somatostatin Receptor Subtype 5 Differentially Present in Pituitary Tumors

Department of Cell Biology, Physiology, and Immunology (M.D.-P., M.D.G., A.J.M.-F., R.M.L., A.Q., F.G.-N., M.M.M., J.P.C.), University of Córdoba, and Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición, E-14014 Córdoba Spain; Department of Endocrinology (S.M.W.), Hospital Sant Pau, Centre for Biomedical Research on Rare Diseases (Centro de Investigación Biomédica en Red de Enfermedades Raras Unit 747), Autonomous University of Barcelona, 08035 Barcelona Spain; Service of Endocrinology and Nutrition (P.B.-L.), Reina Sofia Hospital, 14004 Cordoba, Spain; Division of Endocrinology (A.L.), Virgen del Rocio University Hospital, 41013 Sevilla, Spain; and Department of Pharmacology (S.S.), Julius-Maximilians-University, 97078 Würzburg, Germany

Address all correspondence and requests for reprints to: Dr. Justo P. Castaño, Department of Cell Biology, Physiology, and Immunology, Edificio Severo Ochoa. Planta 3, Campus de Rabanales, University of Córdoba, E-14014 Córdoba, Spain. E-mail: justo{at}uco.es.

Context: Somatostatin and its related peptide cortistatin exert multiple actions on normal and tumoral tissue targets through a family of receptors termed somatostatin receptor (sst)1-5. Despite the considerable advances in the knowledge on these receptors and their (patho)physiological roles, there is still evidence that additional receptors for these peptides should exist to fully explain their actions.

Objective: The growing number of spliced variants found in similar receptor families, often present in tumors, and results from our group obtained on sst5 from other species (pig) led us to explore the existence of new human sst5 isoforms.

Design and Results: A rapid amplification of cDNA ends PCR approach on samples from a human pituitary tumor and a cell line enabled identification of two novel alternatively spliced sst5 receptor variants. The sequences obtained encode putative proteins that correspond to truncated isoforms of five and four transmembrane domains (TMDs), accordingly named sst5TMD5 and sst5TMD4, respectively. Both novel receptors show a differential expression pattern in normal tissues and are also present in pituitary tumors of diverse etiology including nonfunctioning adenomas, corticotropinomas, somatotropinomas, and a prolactinoma. In contrast to the predominant plasma membrane localization of full-length sst5, both sst5TMD5 and sst5TMD4 show a preferentially intracellular localization. Despite their truncated nature, both receptors are functional, as shown by their ability to mediate selective, ligand-induced rises in free cytosolic calcium concentration. Specifically, whereas sst5TMD5 is selectivity activated by somatostatin compared with cortistatin, cells transfected with sst5TMD4 almost exclusively respond to cortistatin and not to somatostatin.

Conclusions: Our results demonstrate the existence of two previously unidentified sst5 spliced variants with distinct distribution in normal tissues and pituitary tumors, unique ligand-selective signaling properties, and subcellular distribution, which could contribute to somatostatin and cortistatin signaling in normal and tumoral cells.