Membrane targeting and coupling of NHE1-integrinalphaIIbbeta3-NCX1 by lipid rafts following integrin-ligand interactions trigger Ca2+ oscillations.
The cyclic calcium release and uptake during calcium oscillation are thought to result from calcium-induced calcium release (CICR); however, it is unclear, especially in nonexcitable cells, how the initial calcium mobilization that triggers CICR occurs. We report here a novel mechanism, other than conventional calcium channels or the phopholipase C-inositol trisphosphate system, for initiating calcium oscillation downstream of integrin signaling. Upon integrin alphaIIbbeta3 binding to fibrinogen ligand or the disintegrin rhodostomin, sodium-proton exchanger NHE1 and sodium-calcium exchanger NCX1 are actively transported to the plasma membrane, and they become physically coupled to integrin alphaIIbbeta3. Lipid raft-dependent mechanisms modulate the membrane targeting and formation of the NHE1-integrin alphaIIbbeta3-NCX1 protein complex. NHE1 and NCX1 within such protein complex are functionally coupled, such that a local increase of sodium concentration caused by NHE1 can drive NCX1 to generate sodium efflux in exchange for calcium influx. The resulting calcium increase inside the cell can then trigger CICR as a prelude to calcium oscillation downstream of integrin alphaIIbbeta3 signaling. Fluorescence resonance energy transfer based on fluorescence lifetime measurements is employed here to monitor the intermolecular interactions among NHE1-integrin alphaIIbbeta3-NCX1, which could not be properly detected using conventional biochemical assays.
Yi
Yung-Hsiang
YH
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 112, Taiwan.
Ho
Pei-Yun
PY
Chen
Tung-Wei
TW
Lin
Wen-Jie
WJ
Gukassyan
Vladimir
V
Tsai
Tsung-Heng
TH
Wang
Da-Wei
DW
Lew
Tien-Shen
TS
Tang
Chih-Yung
CY
Lo
Szecheng J
SJ
Chen
Tsung-Yu
TY
Kao
Fu-Jen
FJ
Lin
Chi-Hung
CH
D000818:Animals; D001683:Biological Clocks / Q000502:physiology; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D005340:Fibrinogen / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate; D021962:Membrane Microdomains / Q000235:genetics / Q000378:metabolism*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism
D027682:Cation Transport Proteins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C490998:SLC9A1 protein, human; D019831:Sodium-Calcium Exchanger; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; C110374:sodium-calcium exchanger 1; D015544:Inositol 1,4,5-Trisphosphate; D005340:Fibrinogen; D012964:Sodium; D010738:Type C Phospholipases; D002118:Calcium