References:
- Liu Q, Bee MS, Schonbrunn A. Site specificity of agonist and second messenger-activated kinases for sst2A somatostatin receptor phosphorylation. Molecular Pharmacology 2009 in press
- Liu Q, Dewi DA, Liu W, Bee MS, Schonbrunn A. Distinct phosphorylation sites in the sst2 somatostatin receptor control internalization, desensitization, and arrestin binding. Molecular Pharmacology 73:292-304, 2008.
- Schonbrunn, A. Selective agnism in somatostatin receptor signaling and regulation. Molecular and Cellular Endocrinology 286:35-39, 2008.
- Cescato R, Schultz S, Waser B, Eltschinger V, Rivier JE, Wester HJ, Culler M, Ginj, Liu Q, Schonbrunn A, Reubi JC Internationalization of sst2, sst3 and sst5 receptors: Effects of somatostatin agonists and antagonists. Journal of Nuclear Medicine 47:502-511, 2006
- Liu Q., Cescato R., Dewi D.A., Rivier j., Reubi J.C. and Schonrbunn A. Receptor signaling and endocytosis are differentially regulared by somatostatin analogs. Molecular Pharmacology 68: 90-101, 2005.
- Korner M., Eltschinger V., Waser b., Schonbrunn A., Reubi J.C. Value of immunohistochemitry for somatostatin receptor subtype sst2A in cancer tissues: lessons from the comparison of two anti-sst2A antibodies with somatostatin receptor autodiography. Am J Surg Pathol. 29(12):1642-1651, 2005.
- Sarret P., Esdaile M.J., McPherson P.S., Schonrunn A., Kreienkamp H-J and Beaudet A. Role of amphiphysin II in somatostatin receptor trafficking in neuroendocrine cells. J.Biol. Chem. 279:8029-8037, 2004.
- Liu Q., Reubi J.C., Wang Y., Knoll B.J., and Schonbrunn A. In vivo phosphorylation of the somatostatin 2A receptor in human tumors. J Clin. Endocrinol Metab. 88:6073-6079, 2003.
Agnes Schonbrunn, Ph.D.
Professor
UTHSC-Medical School, (713) 500 - 7470
Agnes.Schonbrunn@uth.tmc.edu
Somatostatin receptor signaling and regulation
G protein coupled receptors (GPCRs) are the largest class of mammalian cell surface receptors. They are characterized by a common seven-transmembrane domain structure and a signaling mechanism which involves activating trimeric GTP binding proteins called G proteins. GPCRs also comprise the largest family of drug targets: approximately 60% of approved drugs exert their therapeutic effects via GPCRs. Our studies are aimed at understanding the mechanisms by which one particular GPCR family, receptors for the peptide somatostatin, responds to extracellular signals and the manner in which this responsiveness is regulated. Somatostatin is physiologically important for the control of secretion from the pancreas, pituitary and the gastrointestinal tract and acts as a neuromodulator in the brain. Somatostatin receptors are also critical therapeutic targets for the treatment of a variety of cancers and are the only receptors that have been successfully targeted to visualize tumors and their metastases with radiolabeled peptides. In addition, new somatostatin analogs are being actively investigated for the treatment of many different diseases ranging from autoimmune and inflammatory disorders to epilepsy.
Our current studies are focused on three general areas related to somatostatin receptor function. First, we are investigating the role of receptor phosphorylation in the desensitization and internalization of somatostatin receptors as well as in directing receptor signaling. We have identified the regions of the somatostatin 2 receptor (sstr2) that are phosphorylated by somatostatin stimulation and generated a series of receptor constructs in which specific phosphorylation sites were mutated. By expressing these mutant receptors in receptor deficient mammalian cells, we recently showed that different phosphorylation sites are required to regulate receptor endocytosis and receptor signaling. In addition, using fluorescence confocal microscopy, we were able to identify a group of phosphorylated residues that were important for recruiting proteins called arrestins to the receptor. We are now investigating the role of specific receptor phosphorylation sites in receptor signaling and internalization. In a second project, we are characterizing the mechanisms by which somatostatin analogs, in clinical use or under development for clinical applications, are able to elicit different responses upon binding to sstr2. Third, we are extending our studies from model cell lines to animal and human tissues in order to elucidate the mechanisms involved in somatostatin receptor regulation in physiologically and clinically relevant systems. Our hope is that understanding the regulation of somatostatin receptors will provide practically useful insights for the therapeutic and diagnostic applications of somatostatin analogs.
Dr. Schonbrunn's list of GPCRs expressed endogenously in various cell lines is at:
The Endogenous GPCR list
