Shaded are is where EADs are observed in Fig. Our modified I Ks kinetics (solid lines) recapitulate experiment data of I Ks vs.
Realflight 7.5 rc flight simulator iso iso#
Normalized phosphorylation time course of I CaL and I Ks following 1 μM ISO application in the original SS model (solid) and in experimental data (dashed lines) from Lui et al. (PDE, phosphodiesterase PKI, protein kinase inhibitor PP1, protein phosphatase-1 PP2A, protein phosphatase-2A I1, inhibitor-1.) B. β-AR agonists bind to βAR and cause PKA-phosphorylation of numerous cellular targets. Schematic of β-AR signaling network and ECC.
Β-AR model and kinetics of phosphorylationĪ. Our study emphasizes the importance of understanding non-steady state kinetics of several systems in mediating β-adrenergic-induced EADs and arrhythmias. 5) RyR phosphorylation has little effect on either transient EAD type. 4) Blocking phos-pholamban (PLB) phosphorylation has little effect on I CaL-mediated transient EADs, but abolishes SR Ca-release-mediated transient EADs by limiting SR Ca loading. Slowing PLM phosphorylation kinetics abolishes this protective effect. 3) Phospholemman (PLM) phosphorylation decreases both types of EADs by increasing outward Na/K-ATPase current (I NaK) for I CaL-mediated EADs, and reducing intracellular Na and Ca loading for SR Ca-release-mediated EADs. The increased I CaL, SR Ca uptake and action potential duration (APD) raise SR Ca to cause spontaneous SR Ca release, but eventual I Ks activation and APD shortening abolish these EADs. I Ks kinetic mismatch with ISO can also induce transient EADs due to spontaneous sarcoplasmic reticulum (SR) Ca release and Na/Ca exchange current. These EADs disappear at steady state ISO and do not occur during more gradual ISO application. I Ks increases recapitulated experimentally observed ISO-induced transient EADs (which are due to I CaL reactivation). We found that: 1) The faster time course of I CaL vs. Utilizing a biophysically detailed model integrating Ca and β-adrenergic signaling, we investigate how different phos-phorylation kinetics and targets influence β-adrenergic-induced transient EADs. delayed rectifier potassium current (I Ks) effects, but multiple PKA targets complicate mechanistic analysis. Isoproterenol (ISO) stimulation can transiently cause EADs which could result from differential kinetics of L type calcium (Ca) current (I CaL) vs.
Sympathetic stimulation regulates cardiac excitation-contraction coupling in hearts but can also trigger ventricular arrhythmias caused by early afterdepolarizations (EADs) in pathological conditions.