Role of calmodulin in platelet receptor function.
Platelet glycoprotein (GP)Ib-IX-V and GPVI are unique platelet receptors that bind von Willebrand factor or collagen, respectively, and control the initial interaction of circulating platelets with the blood vessel wall in physiology (hemostasis) or pathology (heart attack or stroke). Engagement of GPIbalpha (the major ligand-binding subunit of GPIb-IX-V) by von Willebrand factor or GPVI by collagen, leads to mobilization of cytosolic Ca2+, secretion of platelet agonists such as ADP, cytoskeletal changes, and activation of the platelet integrin alphaIIbbeta3 that mediates von Willebrand factor- or fibrinogen-dependent platelet aggregation. Recent evidence suggests the cytosolic regulatory protein, calmodulin, plays a central role in regulating GPVI or GPIb-IX-V: first, calmodulin directly binds to conserved, juxtamembrane motifs within cytoplasmic domains of both GPVI and GPIb-IX-V (GPIbbeta and GPV subunits) on resting platelets, interactions that dissociate upon platelet activation; second, an intact calmodulin-binding site within GPVI in transfected cells is required for CaCa2+ signaling, but not for GPVI-dependent pathways involving Src family kinases or co-associated FcRgamma-chain; and third, calmodulin regulates metalloproteinase-dependent ectodomain shedding of GPVI and GPV from human platelets. Other vascular cell adhesion receptors, i.e. leukocyte L-selectin, or PECAM-1 (platelet-endothelial cell adhesion molecule-1), also bind calmodulin within the juxtamembrane region of their cytoplasmic tails, an interaction involved in their proteolytic regulation. Further studies should define the precise functional role of calmodulin in thrombus formation initiated by GPIb-IX-V or GPVI.
Gardiner
Elizabeth E
EE
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3168, Australia. elizabeth.gardiner@med.monash.edu.au
Arthur
Jane F
JF
Berndt
Michael C
MC
Andrews
Robert K
RK
D000595:Amino Acid Sequence; D002147:Calmodulin / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000502:physiology; D010980:Platelet Membrane Glycoproteins / Q000502:physiology*; D017386:Sequence Homology, Amino Acid
D002147:Calmodulin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D010980:Platelet Membrane Glycoproteins