Impaired Ca2+-sequestration in dilated cardiomyopathy (review).
Excitation-contraction coupling is the process by which depolarisation of the myocardial surface membrane leads to the release of Ca2+-ions from the sarcoplasmic reticulum, inducing cardiac muscle contraction. This process is made possible by an elaborate system of ion-release, uptake and sequestration that controls the contraction and relaxation cycle of heart muscle fibres. The free intracellular Ca2+-concentration determines the contractile state of the myocardium, and the sequestration of Ca2+-ions into the lumen of the sarcoplasmic reticulum by the Ca2+-ATPase pump units represents a critical step towards the maintenance of normal Ca2+-cycling. The Ca2+-ATPase pump activity is regulated by phospholamban, a small 52-amino acid protein whose phosphorylation state dictates its inhibitory action on the pump. A large body of evidence points to the central role of abnormal Ca2+-ATPase-phospholamban interactions in pathophysiological heart conditions, thereby compromising the contractile state of the cardiac muscle cell. It has been shown that alterations in the oligomeric status of the Ca2+-ATPase and modified interactions between the Ca2+-pump and its regulatory subunit phospholamban underlie the contractile dysfunction that characterises certain forms of dilated cardiomyopathy. Hence, elucidation of interactions within physiological Ca2+-ATPase pump units in normal and diseased myocardium is a vital link in the development of improved diagnostic and therapeutic techniques for dealing with this elusive condition.
Lennon
N J
NJ
Department of Pharmacology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
Ohlendieck
K
K
D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D000099211:Phospholamban