Multiple ways to switch platelet integrins on and off.
In the classical concept of platelet integrin activation, it is considered that unidirectional conformational changes of alpha(IIb)beta(3) and alpha(2)beta(1) regulate the adhesiveness of platelets for fibrin(ogen) and collagen, respectively. Here, we summarize recent evidence that these conformational changes: (i) can also occur in the reverse direction; and (ii) are not independent events. Platelet stimulation through the P2Y(12) receptors provokes only transient alpha(IIb)beta(3) activation via signaling routes involving phosphoinositide 3-kinases and Rap1b. Furthermore, alpha(IIb)beta(3) can be secondarily inactivated in platelets with prolonged high Ca(2+) rises, which expose phosphatidylserine and bind coagulation factors. Thus, platelet stimulation with strong agonists (collagen and thrombin) also results in transient integrin activation. Integrin alpha(2)beta(1) is found to be activated by a mechanism that is directly linked to alpha(IIb)beta(3) activation. Integrin alpha(2)beta(1) can adopt different activation states, depending on the trigger. Conclusively, reversibility and synchrony of platelet integrin activation are newly identified mechanisms to restrict thrombus growth and to allow optimal coagulation factor binding. Back-shifting of activated integrins towards their resting state may be a novel goal of antithrombotic medication.
Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands. jwm.heemskerk@bioch.unimaas.nl
J M E M
JM
Cosemans
B F
BF
Iserbyt
H
H
Deckmyn
J W M
JW
Heemskerk
D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D006801:Humans; D038982:Integrin alpha2beta1 / Q000097:blood / Q000737:chemistry / Q000502:physiology; D016023:Integrins / Q000097:blood* / Q000737:chemistry / Q000502:physiology; D015539:Platelet Activation / Q000502:physiology; D010973:Platelet Adhesiveness / Q000502:physiology; D010974:Platelet Aggregation / Q000502:physiology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000737:chemistry / Q000502:physiology; D011487:Protein Conformation; D018048:Receptors, Purinergic P2 / Q000097:blood / Q000502:physiology; D058925:Receptors, Purinergic P2Y12; D015398:Signal Transduction; D013927:Thrombosis / Q000097:blood / Q000209:etiology
D038982:Integrin alpha2beta1; D016023:Integrins; C548576:P2RY12 protein, human; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12