Identification of Cells Expressing Somatostatin Receptor 2 in the Gastrointestinal Tract of Sstr2 Knockout/lacZ Knockin Mice JEREMY P. ALLEN, 1,2 ALISON J. CANTY, 3 STEFAN SCHULZ, 4 PATRICK P.A. HUMPHREY, 2 PIERS C. EMSON, 1 AND HEATHER M. YOUNG 3 * 1 Department of Neurobiology, The Babraham Institute, Babraham, Cambridge, CB2 4AT, United Kingdom 2 Glaxo Institute of Applied Pharmacology, Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QJ, United Kingdom 3 Department of Anatomy and Cell Biology, University of Melbourne, 3010, VIC, Australia 4 Department of Pharmacology and Toxicology, Otto-von-Guericke University, 39120 Magdeburg, Germany ABSTRACT Somatostatin is found in neurons and endocrine cells in the gastrointestinal tract. The actions of somatostatin are mediated by a family of G-protein– coupled receptors that com- pose five subtypes (SSTR1–5), each of which is encoded by a separate gene. lacZ “knockin” mice, in which the reporter gene lacZ was engineered into the genomic locus of Sstr2 by gene targeting, were used to examine the expression pattern of Sstr2 and identify potential targets for neurally released and hormonal somatostatin in the gastrointestinal tract. In the body of the stomach, a large proportion of epithelial cells and subpopulations of myenteric neurons expressed Sstr2. Double- or triple-labeling with antisera to H + K + ATPase (to identify parietal cells) and/or histidine decarboxylase (to identify enterochromaffin-like [ECL] cells) combined with -galactosidase staining revealed that both parietal cells and ECL cells expressed Sstr2, and these two cell types accounted for almost all of the Sstr2-expressing epithelial cells. Somatostatin inhibits gastric acid secretion. The presence of SSTR2 on both parietal and ECL cells suggests that somatostatin acting on SSTR2 may reduce acid secretion by both acting directly on parietal cells and by reducing histamine release from ECL cells. In the small and large intestine, subpopulations of neurons in the myenteric and submucosal plexuses ex- pressed Sstr2, and many of the Sstr2-expressing myenteric neurons also showed SSTR2(a) immunostaining. Most of Sstr2-expressing neurons in the myenteric plexus showed nitric oxide synthase (NOS) immunoreactivity. Previous studies have shown that NOS neurons are descending interneurons and anally projecting, inhibitory motor neurons. Thus, somatostatin acting at SSTR2 receptors on NOS neurons might modulate descending relaxation. J. Comp. Neurol. 454:329 –340, 2002. © 2002 Wiley-Liss, Inc. Indexing terms: parietal cell; enterochromaffin-like cell; enteric neuron; nitric oxide synthase; motility Grant sponsor: European Contract; Grant number: QLG3-CT-1999- 00908; Grant sponsor: GlaxoSmithkline; Grant sponsor: National Health and Medical Research Council of Australia. Dr. Humphrey’s present address is Advanced Medicine, 901 Gateway Blvd., South San Francisco, CA 94080. *Correspondence to: Heather M. Young, Department of Anatomy and Cell Biology, University of Melbourne, 3010, VIC, Australia. E-mail: h.young@unimelb.edu.au Received 12 September 2001; Revised 25 July 2002; Accepted 23 August 2002 DOI 10.1002/cne.10466 Published online the week of October 28, 2002 in Wiley InterScience (www.interscience.wiley.com). THE JOURNAL OF COMPARATIVE NEUROLOGY 454:329 –340 (2002) © 2002 WILEY-LISS, INC.