CONSTITUTIVE ACTIVATION OF CYCLIC-AMP BUT NOT PHOSPHATIDYLINOSITOL SIGNALING CAUSED BY 4 MUTATIONS IN THE 6TH TRANSMEMBRANE HELIX OF THE HUMAN THYROTROPIN RECEPTOR

被引:44
作者
KOSUGI, S [1 ]
SHENKER, A [1 ]
MORI, T [1 ]
机构
[1] NIDDKD,METAB DIS BRANCH,BETHESDA,MD 20892
关键词
DUAL SIGNALING; G PROTEIN; RECEPTOR ACTIVATION MECHANISM; GLYCOPROTEIN HORMONE RECEPTOR;
D O I
10.1016/0014-5793(94)01286-5
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
Four different somatic mutations (F631C, T632I, D633E, and D633Y) in the putative 6th transmembrane helix of the human thyrotropin receptor (TSHR) were recently described in hyperfunctioning thyroid adenomas [Porcellini et al. (1994) J. Clin. Endocrinol. Metab. 79, 657-661]. We transiently expressed these mutant receptors in Cos-7 cells and measured [I-125]TSH binding, basal and TSH-stimulated cAMP production, and phosphatidylinositol hydrolysis. The concentration of receptors expressed at the cell surface was lower for the mutants than for the wild type (WT) TSHR. Compared to the WT, all four mutant receptors caused a marked increase in basal cAMP levels, but did not increase basal production of inositolphosphates. This suggests that autonomous thyroid function and adenoma formation may be related to constitutive activation of the cAMP pathway alone. A cluster of conserved residues at the base of the 6th transmembrane helix of the TSHR and other glycoprotein hormone receptors appears important for maintaining an inactive receptor conformation.
引用
收藏
页码:291 / 294
页数:4
相关论文
共 32 条
[1]   GUANINE-NUCLEOTIDE AND MAGNESIUM-ION REGULATION OF THE INTERACTION OF GONADOTROPIC AND BETA-ADRENERGIC RECEPTORS WITH THEIR HORMONES - A COMPARATIVE-STUDY USING A SINGLE MEMBRANE SYSTEM [J].
ABRAMOWITZ, J ;
IYENGAR, R ;
BIRNBAUMER, L .
ENDOCRINOLOGY, 1982, 110 (02) :336-346
[2]  
ALLGEIER A, 1994, J BIOL CHEM, V269, P13733
[3]   STRUCTURE AND FUNCTION OF RECEPTORS COUPLED TO G-PROTEINS [J].
BALDWIN, JM .
CURRENT OPINION IN CELL BIOLOGY, 1994, 6 (02) :180-190
[4]   THE PROBABLE ARRANGEMENT OF THE HELICES IN G-PROTEIN-COUPLED RECEPTORS [J].
BALDWIN, JM .
EMBO JOURNAL, 1993, 12 (04) :1693-1703
[5]  
DUPREZ L, 1994, NAT GENET, V7, P369
[6]   INTRAHELICAL HYDROGEN-BONDING OF SERINE, THREONINE AND CYSTEINE RESIDUES WITHIN ALPHA-HELICES AND ITS RELEVANCE TO MEMBRANE-BOUND PROTEINS [J].
GRAY, TM ;
MATTHEWS, BW .
JOURNAL OF MOLECULAR BIOLOGY, 1984, 175 (01) :75-81
[7]   THYROTROPIN, LIKE LUTEINIZING-HORMONE (LH) AND CHORIONIC-GONADOTROPIN (CG), INCREASES CAMP AND INOSITOL PHOSPHATE LEVELS IN CELLS WITH RECOMBINANT HUMAN LH/CG RECEPTOR [J].
HIDAKA, A ;
MINEGISHI, T ;
KOHN, LD .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1993, 196 (01) :187-195
[8]  
Hoflack J, 1993, Drug Des Discov, V10, P157
[9]  
JI T, 1991, J BIOL CHEM, V266, P14953
[10]  
KJELSBERG MA, 1992, J BIOL CHEM, V267, P1430