Endocrinology, Vol 132, 1402-1409, Copyright © 1993 by Endocrine Society

ARTICLES

Amino-terminal parathyroid hormone-related protein: specific binding and cytosolic calcium responses in rat insulinoma cells

G Gaich, JJ Orloff, EJ Atillasoy, WJ Burtis, MB Ganz and AF Stewart
Division of Endocrinology, West Haven Veterans Affairs Medical Center, Connecticut 06516.

PTH-related protein (PTHrP), originally identified through its causative role in human humoral hypercalcemia of malignancy, is now known to be a normal gene product expressed in a wide variety of neuroendocrine, epithelial, and mesoderm-derived tissues. PTHrP gene expression has recently been demonstrated in fetal and adult, benign and malignant, as well as human and rodent pancreatic islets. As in other tissues, the role of PTHrP expression in the normal islet is only beginning to be explored. In the current report, PTHrP expression in the normal rat pancreatic islet was confirmed using an affinity- purified antiserum directed against the N-terminal, biologically active region of the molecule. The effects of PTHrP on the islet were then explored using rat insulinoma (RIN m5F) cells. Synthetic PTHrP-(1-36) bound specifically, but with low affinity (Kd, approximately 10(-7) M) to RIN cell membranes. PTHrP-(1-36) failed to stimulate cAMP production in RIN cells, although RIN cells displayed a normal adenylate cyclase response to glucagon-like peptide-1-(7-36). In contrast, PTHrP-(1-36) induced a rapid dose-dependent rise in intracellular calcium in RIN cells in doses as low as 10(-12)-10(-10) M. These findings 1) confirm that PTHrP is expressed by islet cells, 2) demonstrate that the effects of PTHrP on the pancreatic islet are mediated, as in keratinocytes and lymphocytes, by a receptor related to but distinct from the PTH receptor, and 3) suggest that PTHrP functions in the islet as an autocrine or paracrine factor. Further studies are required to determine the physiological consequences of PTHrP expression by the pancreatic islet.

This article has been cited by other articles:

				T. M. Murray, L. G. Rao, P. Divieti, and F. R. Bringhurst Parathyroid Hormone Secretion and Action: Evidence for Discrete Receptors for the Carboxyl-Terminal Region and Related Biological Actions of Carboxyl- Terminal Ligands Endocr. Rev., February 1, 2005; 26(1): 78 - 113. [Abstract] [Full Text] [PDF]

				Y. Fujinaka, D. Sipula, A. Garcia-Ocana, and R. C. Vasavada Characterization of Mice Doubly Transgenic for Parathyroid Hormone-Related Protein and Murine Placental Lactogen: A Novel Role for Placental Lactogen in Pancreatic {beta}-Cell Survival Diabetes, December 1, 2004; 53(12): 3120 - 3130. [Abstract] [Full Text] [PDF]

				B. Zhang, M. Hosaka, Y. Sawada, S. Torii, S. Mizutani, M. Ogata, T. Izumi, and T. Takeuchi Parathyroid Hormone-Related Protein Induces Insulin Expression Through Activation of MAP Kinase-Specific Phosphatase-1 That Dephosphorylates c-Jun NH2-Terminal Kinase in Pancreatic {beta}-Cells Diabetes, November 1, 2003; 52(11): 2720 - 2730. [Abstract] [Full Text] [PDF]

				M. Castro, F. Dicker, J.-P. Vilardaga, C. Krasel, M. Bernhardt, and M. J. Lohse Dual Regulation of the Parathyroid Hormone (PTH)/PTH-Related Peptide Receptor Signaling by Protein Kinase C and {beta}-Arrestins Endocrinology, October 1, 2002; 143(10): 3854 - 3865. [Abstract] [Full Text] [PDF]

				A. Cebrian, A. Garcia-Ocana, K. K. Takane, D. Sipula, A. F. Stewart, and R. C. Vasavada Overexpression of Parathyroid Hormone-Related Protein Inhibits Pancreatic {beta}-Cell Death In Vivo and In Vitro Diabetes, October 1, 2002; 51(10): 3003 - 3013. [Abstract] [Full Text] [PDF]

				G. J. Strewler The Physiology of Parathyroid Hormone-Related Protein N. Engl. J. Med., January 20, 2000; 342(3): 177 - 185. [Full Text] [PDF]

				D. A. Rubin and H. Juppner Zebrafish Express the Common Parathyroid Hormone/Parathyroid Hormone-related Peptide Receptor (PTH1R) and a Novel Receptor (PTH3R) That Is Preferentially Activated by Mammalian and Fugufish Parathyroid Hormone-related Peptide J. Biol. Chem., October 1, 1999; 274(40): 28185 - 28190. [Abstract] [Full Text] [PDF]

				S. E. Porter, R. L. Sorenson, P. Dann, A. Garcia-Ocana, A. F. Stewart, and R. C. Vasavada Progressive Pancreatic Islet Hyperplasia in the Islet-Targeted, Parathyroid Hormone-Related Protein-Overexpressing Mouse Endocrinology, September 1, 1998; 139(9): 3743 - 3751. [Abstract] [Full Text] [PDF]

				S. Yamamoto, I. Morimoto, K. Zeki, Y. Ueta, H. Yamashita, H. Kannan, and S. Eto Centrally Administered Parathyroid Hormone (PTH)-Related Protein(1-34) But Not PTH(1-34) Stimulates Arginine-Vasopressin Secretion and Its Messenger Ribonucleic Acid Expression in Supraoptic Nucleus of the Conscious Rats Endocrinology, January 1, 1998; 139(1): 383 - 388. [Abstract] [Full Text] [PDF]

				T. Ono, K. Inokuchi, A. Ogura, Y. Ikawa, Y. Kudo, and S. Kawashima Activity-dependent Expression of Parathyroid Hormone-related Protein (PTHrP) in Rat Cerebellar Granule Neurons. REQUIREMENT OF PTHrP FOR THE ACTIVITY-DEPENDENT SURVIVAL OF GRANULE NEURONS J. Biol. Chem., May 30, 1997; 272(22): 14404 - 14411. [Abstract] [Full Text] [PDF]

				S. Yamamoto, I. Morimoto, N. Yanagihara, K. Zeki, T. Fujihira, F. Izumi, H. Yamashita, and S. Eto Parathyroid Hormone-Related Peptide-(1-34) [PTHrP- (1-34)] Induces Vasopressin Release from the Rat Supraoptic Nucleus in Vitro through a Novel Receptor Distinct from a Type I or Type II PTH/PTHrP Receptor Endocrinology, May 1, 1997; 138(5): 2066 - 2072. [Abstract] [Full Text] [PDF]

				T. L. Wu, R. C. Vasavada, K. Yang, T. Massfelder, M. Ganz, S. K. Abbas, A. D. Care, and A. F. Stewart Structural and Physiologic Characterization of the Mid-region Secretory Species of Parathyroid Hormone-related Protein J. Biol. Chem., October 4, 1996; 271(40): 24371 - 24381. [Abstract] [Full Text] [PDF]

				R. C. Vasavada, C. Cavaliere, A. J. D'Ercole, P. Dann, W. J. Burtis, A. L. Madlener, K. Zawalich, W. Zawalich, W. Philbrick, and A. F. Stewart Overexpression of Parathyroid Hormone-related Protein in the Pancreatic Islets of Transgenic Mice Causes Islet Hyperplasia, Hyperinsulinemia, and Hypoglycemia J. Biol. Chem., January 12, 1996; 271(2): 1200 - 1208. [Abstract] [Full Text] [PDF]

				T. B. Usdin, C. Gruber, and T. I. Bonner Identification and Functional Expression of a Receptor Selectively Recognizing Parathyroid Hormone, the PTH2 Receptor J. Biol. Chem., June 30, 1995; 270(26): 15455 - 15458. [Abstract] [Full Text] [PDF]

				L. L. Plawner, W. M. Philbrick, W. J. Burtis, A. E. Broadus, and A. F. Stewart Cell Type-specific Secretion of Parathyroid Hormone-related Protein via the Regulated versus the Constitutive Secretory Pathway J. Biol. Chem., June 9, 1995; 270(23): 14078 - 14084. [Abstract] [Full Text] [PDF]