Impaired Ca2+-sequestration in dilated cardiomyopathy (Review)

Excitation-contraction coupling is the process by which depolarisation of t he myocardial surface membrane leads to the release of Ca2+-ions from the s arcoplasmic reticulum, inducing cardiac muscle contraction. This process is made possible by an elaborate system of ion-release, uptake and sequestrat ion that controls the contraction and relaxation cycle of heart muscle fibr es. The free intracellular Ca2+-concentration determines the contractile st ate of the myocardium, and the sequestration of Ca2+-ions into the lumen of the sarcoplasmic reticulum by the Ca2+-ATPase pump units represents a crit ical step towards the maintenance of normal Ca2+-cycling. The Ca2+-ATPase p ump activity is regulated by phospholamban, a small 52-amino acid protein w hose phosphorylation state dictates its inhibitory action on the pump. A la rge body of evidence points to the central role of abnormal Ca2+-ATPase-pho spholamban interactions in pathophysiological heart conditions, thereby com promising the contractile state of the cardiac muscle cell. It has been sho wn that alterations in the oligomeric status of the Ca2+-ATPase and modifie d interactions between the Ca2+-pump and its regulatory subunit phospholamb an underlie the contractile dysfunction that characterises certain forms of dilated cardiomyopathy. Hence, elucidation of interactions within physiolo gical Ca2+-ATPase pump units in normal and diseased myocardium is a vital l ink in the development of improved diagnostic and therapeutic techniques fo r dealing with this elusive condition.