G protein-coupled receptors sense fluid shear stress in endothelial cells

被引:348
作者
Chachisvilis, Mirianas [1 ]
Zhang, Yan-Liang [1 ]
Frangos, John A. [1 ]
机构
[1] Jolla Bioengn Inst, La Jolla, CA 92037 USA
关键词
conformational transition; ligand-independent activation; mechanochemical signal transduction; plasma membrane; bradykinin;
D O I
10.1073/pnas.0607224103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Hemodynamic shear stress stimulates a number of intracellular events that both regulate vessel structure and influence development of vascular pathologies. The precise molecular mechanisms by which endothelial cells transduce this mechanical stimulus into intracellular biochemical response have not been established. Here, we show that mechanical perturbation of the plasma membrane leads to ligand-independent conformational transitions in a G protein-coupled receptor (GPCR). By using time-resolved fluorescence microscopy and GPCR conformation-sensitive FRET we found that stimulation of endothelial cells with fluid shear stress, hypotonic stress, or membrane fluidizing agent leads to a significant increase in activity of bradykinin B-2 GPCR in endothelial cells. The GPCR conformational dynamics was detected by monitoring redistribution of GPCRs between inactive and active conformations in a single endothelial cell under fluid shear stress in real time. We show that this response can be blocked by a B-2-selective antagonist. Our data demonstrate that changes in cell membrane tension and membrane fluidity affect conformational dynamics of GPCRs. Therefore, we suggest that GPCRs are involved in mediating primary mechanochemical signal transduction in endothelial cells. We anticipate our experiments to be a starting point for more sophisticated studies of the effects of changes in lipid bilayer environment on GPCR conformational dynamics. Furthermore, because GPCRs are a major target of drug development, a detailed characterization of mechanochemical signaling via the GPCR pathway will be relevant for the development of new antiatherosclerosis drugs.
引用
收藏
页码:15463 / 15468
页数:6
相关论文
共 46 条
  • [1] SHEAR STRESS-INDUCED REORGANIZATION OF THE SURFACE-TOPOGRAPHY OF LIVING ENDOTHELIAL-CELLS IMAGED BY ATOMIC-FORCE MICROSCOPY
    BARBEE, KA
    DAVIES, PF
    LAL, R
    [J]. CIRCULATION RESEARCH, 1994, 74 (01) : 163 - 171
  • [2] Decreased flow-dependent dilation in carotid arteries of tissue kallikrein-knockout mice
    Bergaya, S
    Meneton, P
    Bloch-Faure, M
    Mathieu, E
    Alhenc-Gelas, F
    Lévy, BI
    Boulanger, CM
    [J]. CIRCULATION RESEARCH, 2001, 88 (06) : 593 - 599
  • [3] Bevan JA., 1995, FLOW DEPENDENT REGUL
  • [4] Probing the molecular-scale lipid bilayer response to shear flow using nonequilibrium molecular dynamics
    Blood, PD
    Ayton, GS
    Voth, GA
    [J]. JOURNAL OF PHYSICAL CHEMISTRY B, 2005, 109 (39) : 18673 - 18679
  • [5] INCREASE IN MEMBRANE FLUIDITY IN LIPOSOMES AND PLANT PROTOPLASTS UPON OSMOTIC SWELLING
    BOROCHOV, A
    BOROCHOV, H
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA, 1979, 550 (03) : 546 - 549
  • [6] Conformational energetics of rhodopsin modulated by nonlamellar-forming lipids
    Botelho, AV
    Gibson, NJ
    Thurmond, RL
    Wang, Y
    Brown, MF
    [J]. BIOCHEMISTRY, 2002, 41 (20) : 6354 - 6368
  • [7] Shear stress induces a time- and position-dependent increase in endothelial cell membrane fluidity
    Butler, PJ
    Norwich, G
    Weinbaum, S
    Chien, S
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2001, 280 (04): : C962 - C969
  • [8] FLOW-MEDIATED ENDOTHELIAL MECHANOTRANSDUCTION
    DAVIES, PF
    [J]. PHYSIOLOGICAL REVIEWS, 1995, 75 (03) : 519 - 560
  • [9] Requirement of rigid-body motion of transmembrane helices for light activation of rhodopsin
    Farrens, DL
    Altenbach, C
    Yang, K
    Hubbell, WL
    Khorana, HG
    [J]. SCIENCE, 1996, 274 (5288) : 768 - 770
  • [10] Spontaneous human B2 bradykinin receptor activity determines the action of partial agonists as agonists or inverse agonists - Effect of basal desensitization
    Fathy, DB
    Leeb, T
    Mathis, SA
    Leeb-Lundberg, LMF
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (42) : 29603 - 29606