New roles of calsequestrin and triadin in cardiac muscle.
Cardiac calsequestrin (Casq2) and triadin are proteins located in specialized areas of the sarcoplasmic reticulum (SR) where the SR forms junctions with the sarcolemma (junctional SR). Casq2, triadin and junctin form a protein complex that is associated with cardiac ryanodine receptor 2 (RyR2) SR Ca(2+) release channels. This review highlights new insights of the roles of triadin and Casq2 derived from gene-targeted knock-out and knock-in mouse models that have recently become available. Characterization of the mouse models suggests that Casq2's contribution to SR Ca(2+) storage and release during excitation-contraction coupling is largely dispensable. Casq2's primary role appears to be in protecting the heart against premature Ca(2+) release and triggered arrhythmias. Furthermore, both cardiac Casq2 and triadin are important for the structural organization of the SR, which had previously not been recognized. In particular, ablation of triadin causes a 50% reduction in the extent of the junctional SR, which results in impaired excitation-contraction coupling at the level of the myocyte. While catecholamines could normalize contractile function by increasing I(Ca) and SR Ca(2+) content, it comes at the price of an increased risk for spontaneous Ca(2+) releases in triadin knock-out myocytes and catecholamine-induced ventricular arrhythmias in triadin knock-out mice.
Knollmann
Björn C
BC
Depts. of Medicine and Pharmacology, Vanderbilt Univ., Nashville, TN 37232, USA. bjorn.knollmann@vanderbilt.edu
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology; D002155:Calsequestrin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000502:physiology; D008955:Models, Cardiovascular; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009200:Myocardial Contraction / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D002135:Calcium-Binding Proteins; D002155:Calsequestrin; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C498270:Trdn protein, mouse; C514388:casq2 protein, mouse; C498841:Asph protein, mouse; D006899:Mixed Function Oxygenases