The Integrative Physiology of the Plasma Membrane Calcium ATPase in Platelets
Author(s)
Solomon, Antonia Bibiana
Type
Thesis
Abstract
Plasma Membrane Calcium-ATPases (PMCA’s) extrude calcium from a variety of
cell types and have recently been shown to regulate signalling events and function in
the cardiovascular system. PMCA (isoform 4) is expressed in platelets, however its
functional role remains undefined.
The aims of this project were to investigate the roles of PMCA in regulating calcium
homeostasis and human platelet function during the various stages of platelet
activation by evaluating the effects of a pharmacological inhibitor of PMCA,
carboxyeosin, upon a range of in vitro and in vivo assays. Additional experiments
were performed to determine the functional consequences of PMCA4 ablation using
platelets from PMCA4 knock-out mice and the roles of PMCA were contrasted with
other calcium transporters. Finally, the mechanism of action of PMCA in platelets
was investigated by integrating molecular studies with the functional assays.
The findings presented in this thesis suggest that PMCA plays an important role in
regulating calcium both basally and during platelet activation. PMCA positively
regulates platelet aggregation through the modulation of negative signalling
pathways but negatively regulates the earlier and later stages of activation measured
as adhesion and clot retraction respectively. PMCA also regulates platelet function
in vivo. Experiments in PMCA4 knock-out mice implicated the PMCA4 isoform in
the regulation of platelet function. Comparison of PMCA, SERCA (sarcoendoplasmic
reticulum ATPase) and NCX (Na+/Ca2+-exchanger) pumps indicated
that all three calcium transporters play pivotal but contrasting roles in platelet
function and calcium homeostasis.
In conclusion, PMCA is a key regulator of calcium homeostasis and
differentially regulates the various stages of platelet activation. PMCA
regulates intracellular signalling events in platelets although the mechanisms
remain to be fully determined. PMCA is therefore a key modulator of
haemostasis and thrombosis and may be a potential target in the treatment of
conditions such as arterial thrombosis and stroke.
cell types and have recently been shown to regulate signalling events and function in
the cardiovascular system. PMCA (isoform 4) is expressed in platelets, however its
functional role remains undefined.
The aims of this project were to investigate the roles of PMCA in regulating calcium
homeostasis and human platelet function during the various stages of platelet
activation by evaluating the effects of a pharmacological inhibitor of PMCA,
carboxyeosin, upon a range of in vitro and in vivo assays. Additional experiments
were performed to determine the functional consequences of PMCA4 ablation using
platelets from PMCA4 knock-out mice and the roles of PMCA were contrasted with
other calcium transporters. Finally, the mechanism of action of PMCA in platelets
was investigated by integrating molecular studies with the functional assays.
The findings presented in this thesis suggest that PMCA plays an important role in
regulating calcium both basally and during platelet activation. PMCA positively
regulates platelet aggregation through the modulation of negative signalling
pathways but negatively regulates the earlier and later stages of activation measured
as adhesion and clot retraction respectively. PMCA also regulates platelet function
in vivo. Experiments in PMCA4 knock-out mice implicated the PMCA4 isoform in
the regulation of platelet function. Comparison of PMCA, SERCA (sarcoendoplasmic
reticulum ATPase) and NCX (Na+/Ca2+-exchanger) pumps indicated
that all three calcium transporters play pivotal but contrasting roles in platelet
function and calcium homeostasis.
In conclusion, PMCA is a key regulator of calcium homeostasis and
differentially regulates the various stages of platelet activation. PMCA
regulates intracellular signalling events in platelets although the mechanisms
remain to be fully determined. PMCA is therefore a key modulator of
haemostasis and thrombosis and may be a potential target in the treatment of
conditions such as arterial thrombosis and stroke.
Date Issued
2011-03
Date Awarded
2011-04
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Emerson, Mike
Mitchell, Jane
Creator
Solomon, Antonia Bibiana
Publisher Department
Medicine: National Heart and Lung Institute
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)