Phospholamban phosphorylation by CaMKII under pathophysiological conditions.
Sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA2a) transports Ca2+ into the SR, decreasing the cytosolic Ca2+ during relaxation and increasing the SR Ca2+ available for contraction. SERCA2a activity is regulated by phosphorylation of another SR protein: Phospholamban (PLN). Dephosphorylated PLN inhibits SERCA2a. Phosphorylation of PLN by either cAMP or cGMP-dependent protein kinase at Ser16 or the Ca2+-calmodulin-dependent protein kinase (CaMKII), at Thr17, relieves this inhibition, increasing SR Ca2+ uptake and SR Ca2+ load. Thus, PLN is a major player in the regulation of myocardial relaxation and contractility. This review will examine the main aspects of the role of CaMKII and Thr17 site of PLN, on different pathophysiological conditions: acidosis, ischemia/reperfusion (I/R) and heart failure (HF). Whereas CaMKII-activation and PLN phosphorylation contribute to the functional recovery during acidosis and stunning, CaMKII results detrimental in the irreversible I/R injury, producing apoptosis and necrosis. Phosphorylation of Thr17 residue of PLN and CaMKII activity vary in the different models of HF. The possible role of these changes in the depressed cardiac function of HF will be discussed.
Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Medicas, Universidad Nacional de La Plata, 60 y 120, 1900 La Plata, Argentina. lvittone@atlas.med.unlp.edu.ar
Leticia
L
Vittone
Cecilia
C
Mundina-Weilenmann
Alicia
A
Mattiazzi
D000138:Acidosis / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D017682:Myocardial Stunning / Q000503:physiopathology; D010766:Phosphorylation; D015427:Reperfusion Injury / Q000503:physiopathology*; D013379:Substrate Specificity; D013912:Threonine / Q000378:metabolism; D014661:Vasoconstriction; D014664:Vasodilation; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D013912:Threonine; D000099211:Phospholamban