Sorcin, a ~22-kDa Ca-binding protein widely expressed in mammalian tissues, is a novel regulator of excitation-contraction coupling in the heart. We have previously characterized the association of sorcin with the cardiac Ca release channel/ryanodine receptor (RyR2) of the sarcoplasmic reticulum. Using in vitro and in vivo functional assays, we found that sorcin 1) binds to RyR2s directly and with fast kinetics, rapidly inhibiting single channel activity, 2) undergoes Ca-dependent conformational changes, thereby modulating its affinity for yR2s, 3) localizes to z-lines in ventricular cardiomyocytes, 4) translocates from soluble to membrane bound protein targets in a Ca-dependent manner, 5) attenuates Ca sparks and Ca transients in intact cells, 6) is Phosphorylated by PKA, which in turn attenuates its inhibitory effect on RyR2s. Recently, we generated a Mouse line with genetic ablation of SRI, the gene encoding for sorcin in humans and multiple animal species. Under basal conditions, ventricular myocytes from these mice show apparently normal Ca transients and contractions. However, the apparent equilibrium in sorcin-ko mice is precarious, because a) exercise tests quickly throw these mice into aberrant cardiac electrical activity (tachyarrhythmias and sudden cardiac arrest), b) beta adrenergic stimulation of sorcin-ko hearts leads to arrhythmias and fibrillation, and c) isolated cardiomyocytes stimulated with Isoproterenol display Ca oscillations, aftercontractions, and delayed afterdepolarizations. Thus, ablation of sorcin leaves basal cardiac activity almost intact, but leads to increased automaticity. The goal of this proposal is to determine the functional role of sorcin in e-c coupling of the heart, in great part y identifying the molecular and cellular functions affected by its absence, and dissecting the mechanisms that lead to aberrant electrical behavior. We hypothesize that in normal ventricular myocytes, sorcin binds to at least four key players of e-c coupling, with its overall effect being that of a cytosolic Ca2+ sweeper. We propose: 1) to identify the molecular determinants of sorcin interaction with key proteins of e-c coupling;and 2) to determine the integrated role of sorcin in normal e-c coupling, and the pathophysiological mechanisms that lead to aberrant electrical behavior in its absence.
Calcium-dependent arrhythmias are common events in many cardiac diseases such as heart failure and hypertrophic cardiomyopathy. By determining the mechanisms of action of sorcin, a calcium-binding protein of the heart that regulates several calcium channels and transporters, this research will provide fundamental knowledge on the cellular mechanisms that initiate and perpetuate calcium-dependent arrhythmias.
|Chen, Xi; Weber, Craig; Farrell, Emily T et al. (2018) Sorcin ablation plus ?-adrenergic stimulation generate an arrhythmogenic substrate in mouse ventricular myocytes. J Mol Cell Cardiol 114:199-210|
|Valdivia, Héctor H; Valdivia, Carmen R (2018) Tetracaine derivatives for catecholaminergic polymorphic ventricular tachycardia: New drugs for correction of diastolic Ca2+ leak? Heart Rhythm 15:587-588|
|Alvarado, Francisco J; Valdivia, Carmen R; Valdivia, Héctor H (2018) Navigating the Sea of Long Noncoding RNAs: ZFAS1, Friend or Foe? Circ Res 122:1327-1329|
|Avula, Uma Mahesh R; Hernandez, Jonathan J; Yamazaki, Masatoshi et al. (2018) Atrial Infarction-Induced Spontaneous Focal Discharges and Atrial Fibrillation in Sheep: Role of Dantrolene-Sensitive Aberrant Ryanodine Receptor Calcium Release. Circ Arrhythm Electrophysiol 11:e005659|
|Vargas-Jaimes, Leonel; Xiao, Liang; Zhang, Jing et al. (2017) Recombinant expression of Intrepicalcin from the scorpion Vaejovis intrepidus and its effect on skeletal ryanodine receptors. Biochim Biophys Acta Gen Subj 1861:936-946|
|Lavorato, Manuela; Iyer, V Ramesh; Dewight, Williams et al. (2017) Increased mitochondrial nanotunneling activity, induced by calcium imbalance, affects intermitochondrial matrix exchanges. Proc Natl Acad Sci U S A 114:E849-E858|
|Aistrup, Gary L; Arora, Rishi; Grubb, Søren et al. (2017) Triggered intracellular calcium waves in dog and human left atrial myocytes from normal and failing hearts. Cardiovasc Res 113:1688-1699|
|Alvarado, Francisco J; Chen, Xi; Valdivia, Héctor H (2017) Ablation of the cardiac ryanodine receptor phospho-site Ser2808 does not alter the adrenergic response or the progression to heart failure in mice. Elimination of the genetic background as critical variable. J Mol Cell Cardiol 103:40-47|
|Bao, Yangyang; Willis, B Cicero; Frasier, Chad R et al. (2016) Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias. Circ Arrhythm Electrophysiol 9:|
|Wu, Yuejin; Valdivia, Héctor H; Wehrens, Xander H T et al. (2016) A Single Protein Kinase A or Calmodulin Kinase II Site Does Not Control the Cardiac Pacemaker Ca2+ Clock. Circ Arrhythm Electrophysiol 9:e003180|
Showing the most recent 10 out of 18 publications