SIGNAL-TRANSDUCTION OF THE GLP-1-RECEPTOR CLONED FROM A HUMAN INSULINOMA

被引:51
作者
VANEYLL, B
LANKATBUTTGEREIT, B
BODE, HP
GOKE, R
GOKE, B
机构
[1] UNIV MARBURG,CLIN RES UNIT GASTROINTESTINAL ENDOCRINOL,D-35033 MARBURG,GERMANY
[2] UNIV MARBURG,DEPT PHARMACOL,D-35033 MARBURG,GERMANY
关键词
HUMAN INSULINOMA; GLP-1; RECEPTOR; COS-7; CELL; CHL CELL; CALCIUM; CAMP;
D O I
10.1016/0014-5793(94)00553-2
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
GLP-1 (glucagon-like peptide 1 (7-36) amide) plays an important role in the regulation of insulin secretion and proinsulin gene expression of pancreatic beta-cells. Patients with insulinoma tumors show-uncontrolled insulin hypersecretion. This study demonstrates the molecular cloning of a cDNA for the GLP-1 receptor from a human insulinoma employing a lambda-gt11 cDNA library. The cloned cDNA encoded a seven transmembrane domain protein of 463 amino acids which showed high homology to the GLP-1 receptor in normal human pancreas. Four amino acid exchanges were found in comparison to a receptor sequence obtained from regular pancreatic islets. When transfected transiently into COS-7 or stably into fibroblast CHL cells a high affinity receptor was expressed which coupled to the adenylate cyclase with normal basal cAMP and increasing intracellular cAMP levels under GLP-1 stimulation. The receptor accepted GLP-1 and the non-mammalian agonist exendin-4 as high affinity ligands. In transfected COS-7 cells, GLP-1 did not influence intracellular calcium, whereas in the stably transfected fibroblasts GLP-1 transiently increased intracellular calcium to a small extent. The understanding of GLP-1 receptor regulation and signal transduction will aid in the discovery of compounds that act as agonists of the GLP-1 receptor for potential use in the treatment of diabetes and will facilitate the understanding of its expression under normal and pathophysiological conditions.
引用
收藏
页码:7 / 13
页数:7
相关论文
共 54 条
[1]   GLUCAGON-LIKE PEPTIDE - A THERAPEUTIC GLIMMER [J].
AMIEL, SA .
LANCET, 1994, 343 (8888) :4-5
[2]   PROTEIN-KINASE-C ACTIVATES CAPACITATIVE CALCIUM-ENTRY IN THE INSULIN-SECRETING CELL-LINE RINM5F [J].
BODE, HP ;
GOKE, B .
FEBS LETTERS, 1994, 339 (03) :307-311
[3]   SINGLE-STEP METHOD OF RNA ISOLATION BY ACID GUANIDINIUM THIOCYANATE PHENOL CHLOROFORM EXTRACTION [J].
CHOMCZYNSKI, P ;
SACCHI, N .
ANALYTICAL BIOCHEMISTRY, 1987, 162 (01) :156-159
[4]   MUTATIONS IN G-PROTEIN-LINKED RECEPTORS - NOVEL INSIGHTS ON DISEASE [J].
CLAPHAM, DE .
CELL, 1993, 75 (07) :1237-1239
[5]  
COMI RJ, 1986, EXOCRINE PANCREAS, P741
[6]   CLONING AND FUNCTIONAL EXPRESSION OF THE HUMAN GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR [J].
DILLON, JS ;
TANIZAWA, Y ;
WHEELER, MB ;
LENG, XH ;
LIGON, BB ;
RABIN, DU ;
YOOWARREN, H ;
PERMUTT, MA ;
BOYD, AE .
ENDOCRINOLOGY, 1993, 133 (04) :1907-1910
[7]   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
[8]   GLYCOSYLATION OF VIP RECEPTORS - A MOLECULAR-BASIS FOR RECEPTOR HETEROGENEITY [J].
FABRE, C ;
ELBATTARI, A ;
KARAMANOS, Y ;
COUVINEAU, A ;
SALOMON, R ;
LABURTHE, M ;
MARVALDI, J ;
PICHON, J ;
LUIS, J .
PEPTIDES, 1993, 14 (03) :483-489
[9]   FUNCTIONAL RECEPTORS FOR THE INSULINOTROPIC HORMONE GLUCAGONLIKE PEPTIDE-I(7-37) ON A SOMATOSTATIN SECRETING CELL-LINE [J].
FEHMANN, HC ;
HABENER, JF .
FEBS LETTERS, 1991, 279 (02) :335-340
[10]   INSULINOTROPIC HORMONE GLUCAGON-LIKE PEPTIDE-I(7-37) STIMULATION OF PROINSULIN GENE-EXPRESSION AND PROINSULIN BIOSYNTHESIS IN INSULINOMA BETA-TC-1 CELLS [J].
FEHMANN, HC ;
HABENER, JF .
ENDOCRINOLOGY, 1992, 130 (01) :159-166