Somatostatin receptor subtype-5 mediates inhibition of peptide YY secretion from rat intestinal cultures.
Somatostatin-14 (S-14) and somatostatin-28 (S-28) bind to five distinct membrane receptors (SSTRs), but S-28 has higher affinity for SSTR-5. Whether S-28 acting through SSTR-5 regulates inhibition of peptide YY (PYY) secretion was tested in fetal rat intestinal cell cultures. S-28 and S-14 caused dose-dependent inhibition of PYY secretion stimulated by gastrin-releasing peptide, but S-28 was more potent than S-14 (EC(50) 0.04 vs. 13.2 nM). PYY was inhibited by two analogs with affinity for SSTR-5, BIM-23268 and BIM-23052, more potently than S-14 and as effectively as S-28. The SSTR-5 analog L-362855 suppressed PYY equivalent only to S-14, but the structurally related peptide L-372588 (Phe to Tyr at position 2) was equipotent to S-28, whereas L-372587 (Phe to Tyr at position 7) caused no inhibition. An SSTR-2 analog decreased PYY secretion similar to S-14, and an SSTR-3 analog was ineffective. PYY secretion stimulated by phorbol 12-myristate 13-acetate and by forskolin was also more potently suppressed by S-28 and the octapeptide SSTR-5 analogs. The results indicate that S-28 mediates inhibition of gastrin-releasing peptide-stimulated PYY secretion through activation of SSTR-5 and includes suppression of cAMP- and protein kinase C-dependent pathways. Substitution of a single hydroxyl group confers differences in SSTR-5 agonist properties, suggesting region specificity for the intrinsic activity of this receptor subtype.
Chisholm
C
C
Department of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Greenberg
G R
GR
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D019886:Gastrin-Releasing Peptide / Q000378:metabolism; D006728:Hormones / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D009568:Nitrendipine / Q000494:pharmacology; D019894:Peptide YY / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D053561:Somatostatin-28; D013329:Structure-Activity Relationship; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
C114314:BIM 23052; C121506:BIM 23268; D002273:Carcinogens; D006728:Hormones; C091739:L 362855; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; D014665:Vasodilator Agents; D019894:Peptide YY; D005576:Colforsin; D013004:Somatostatin; D053561:Somatostatin-28; D019886:Gastrin-Releasing Peptide; C094573:somatostatin receptor 5; D009568:Nitrendipine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate