DETERMINANTS OF [ARG(2)]PTH-(1-34) BINDING AND SIGNALING IN THE TRANSMEMBRANE REGION OF THE PARATHYROID-HORMONE RECEPTOR

被引:75
作者
GARDELLA, TJ [1 ]
JUPPNER, H [1 ]
WILSON, AK [1 ]
KEUTMANN, HT [1 ]
ABOUSAMRA, AB [1 ]
SEGRE, GV [1 ]
BRINGHURST, FR [1 ]
POTTS, JT [1 ]
NUSSBAUM, SR [1 ]
KRONENBERG, HM [1 ]
机构
[1] HARVARD UNIV, SCH MED, BOSTON, MA 02114 USA
关键词
D O I
10.1210/en.135.3.1186
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Previously, we reported that [Arg(2)]PTH-(1-34) bound to the rat osteosarcoma cell line, ROS 17/2.8, with 2-fold higher apparent affinity than it did to the opossum kidney cell line, OK, yet the analog was only a weak partial agonist for cAMP stimulation with ROS 17/2.8 cells, whereas it was a full cAMP agonist with OK cells. These results suggested that the rat and opossum PTH receptors differ in a region recognized by the hormone's amino-terminus. In this report we show that the cloned PTH receptors derived from ROS 17/2.8 and OK cells, expressed in COS-7 cells, also displayed altered responses to [Arg(2)] PTH-(1-34). Thus, [Arg(2)]PTH-(1-34) bound to the cloned rat PTH receptor with 7-fold higher affinity than it did to the cloned opossum PTH receptor, and in cAMP stimulation assays, it was a much weaker agonist with the rat receptor than it was with the opossum receptor. Studies with rat/opossum PTH receptor chimeras suggested that the membrane-spanning region of the receptor contributed to the different binding and signaling responses to [Arg(2)]PTH-(1-34). Point mutation analysis identified three sites in or near the extracellular ends of transmembrane domains V and VI, which specifically affected [Arg(2)] PTH-(1-34) binding and signaling.
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页码:1186 / 1194
页数:9
相关论文
共 34 条
[1]   EXPRESSION CLONING OF A COMMON RECEPTOR FOR PARATHYROID-HORMONE AND PARATHYROID HORMONE-RELATED PEPTIDE FROM RAT OSTEOBLAST-LIKE CELLS - A SINGLE RECEPTOR STIMULATES INTRACELLULAR ACCUMULATION OF BOTH CAMP AND INOSITOL TRISPHOSPHATES AND INCREASES INTRACELLULAR FREE CALCIUM [J].
ABOUSAMRA, AB ;
JUPPNER, H ;
FORCE, T ;
FREEMAN, MW ;
KONG, XF ;
SCHIPANI, E ;
URENA, P ;
RICHARDS, J ;
BONVENTRE, JV ;
POTTS, JT ;
KRONENBERG, HM ;
SEGRE, GV .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (07) :2732-2736
[2]   A SINGLE AMINO-ACID OF THE CHOLECYSTOKININ-B GASTRIN RECEPTOR DETERMINES SPECIFICITY FOR NONPEPTIDE ANTAGONISTS [J].
BEINBORN, M ;
LEE, YM ;
MCBRIDE, EW ;
QUINN, SM ;
KOPIN, AS .
NATURE, 1993, 362 (6418) :348-350
[3]   EXPRESSION CLONING OF A HUMAN CORTICOTROPIN-RELEASING-FACTOR RECEPTOR [J].
CHEN, RP ;
LEWIS, KA ;
PERRIN, MH ;
VALE, WW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (19) :8967-8971
[4]   MODEL SYSTEMS FOR THE STUDY OF 7-TRANSMEMBRANE-SEGMENT RECEPTORS [J].
DOHLMAN, HG ;
THORNER, J ;
CARON, MG ;
LEFKOWITZ, RJ .
ANNUAL REVIEW OF BIOCHEMISTRY, 1991, 60 :653-688
[5]  
FONG TM, 1992, J BIOL CHEM, V267, P25664
[6]  
FONG TM, 1993, NATURE, V362, P350
[7]  
GARDELLA TJ, 1991, J BIOL CHEM, V266, P13141
[8]   DIFFERENT BINDING EPITOPES ON THE NK1 RECEPTOR FOR SUBSTANCE-P AND A NONPEPTIDE ANTAGONIST [J].
GETHER, U ;
JOHANSEN, TE ;
SNIDER, RM ;
LOWE, JA ;
NAKANISHI, S ;
SCHWARTZ, TW .
NATURE, 1993, 362 (6418) :345-348
[9]  
GETHER U, 1993, J BIOL CHEM, V268, P7893
[10]  
GOLTZMANN D, 1975, J BIOL CHEM, V250, P3199