The Ca-Calmodulin Dependent Protein Kinase II System of Skeletal Muscle Sarcoplasmic Reticulum

It is well known that skeletal muscle sarcoplasmic reticulum (SR) contains a Cacalmodulin (CaM) dependent protein kinase (CaMKII) system. In the last twenty years, much experimental work has clarified the biochemical-functional properties of this kinase system. SR-bound CaMKII is formed by the holoenzyme and by anchoring proteins, called αKAP. The holoenzyme is composed by a muscle specific form of β subunit (βΜ), and by γ and δ subunits. In rabbit skeletal muscle, βΜ seems to be expressed in greater amounts in slow-twitch muscle. Two isoforms of αKAP of 23-21 kDa are present in isolated SR fragments of rabbit fast-twitch muscle, whereas only the 23 kDa αKAP splice variant is expressed in slow-twitch muscle. Based on biochemical work on isolated SR vesicles, the kinetic properties of SR-bound CaMKII do not significantly differ from those of CaMKII in other tissues. CaMKII is localized on the cytoplasmic side of SR membranes, and is ubiquitously distributed between longitudinal SR and junctional SR. In slow-twitch muscle, CaMKII is mainly involved in regulation of SR Ca-transport, as indicated by phosphorylation of SERCA2a isoform of Ca-ATPase and of SERCA2a-regulatory protein phospholamban. In fast-twitch muscle, the main role of CaMKII seems to be the control of Carelease. Much experimental evidence seems to negate that ryanodine receptor/SR Carelease channel of skeletal muscle (RyR1) is a substrate of phosphorylation of endogenous CaMKII. The main undisputed, junctional SR-specific protein substrate of CaMKII is triadin, which interacts structurally and functionally with RyR1. The functional effect on RyR1 of CaMKII-dependent phosphorylation of junctional SR membranes remains somewhat controversial, even though the bulk of experimental evidence suggests a negative regulation of the calcium channel by the kinase. Additional protein substrates of SR-bound CaMKII are histidine-rich Ca-binding protein, glycogen synthase and 21 kDa αKAP. Therefore, SR-bound CaMKII is involved in regulation of Ca-homeostasis and, likely, of glucose metabolism. A putative role in regulation of gene expression remains to be established.