IP3 receptor, NOX2 and calcium signaling domains in atrial physiology and pathophysiology

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PROJECT SUMMARY/ABSTRACT Atrial excitation-contraction coupling (ECC) and sarcoplasmic reticulum (SR) Ca release have unique features and are distinctly different from ventricular ECC. During ECC the action potential (AP) initiates Ca release from the SR Ca stores primarily through the ryanodine receptor (RyR) Ca release channels. The atrial SR has a second, albeit less abundant Ca release channel, the inositol-1,4,5-trisphosphate receptor (IP3R). IP3R induced Ca release (IICR) participates in ECC but also has non-ECC functions, including contribution to pacemaker activity, mitochondrial Ca signaling, and regulation of transcription factor activity important for pathophysiological atrial remodeling. IICR has sex-specific attributes and exerts positive inotropic effects, but also facilitates proarrhythmic Ca release. IICR is upregulated in atrial tissue in heart failure (HF), which facilitates SR Ca release and enhances atrial contraction, but also leads to increased risk of alternans and atrial fibrillation. The cardiac IP3R is target of post-translational modifications. New preliminary data demonstrate that in atrial myocytes the IP3R is co-regulated by IP3 and ROS provided by NADPH-oxidase type 2 (NOX2) and involves ROS-dependent IP3R glutathionylation. The overall goal of this proposal will test the hypothesis that in atrial tissue a NOX2/ROS/IP3R signaling domain is responsible for the positive inotropic and proarrhythmic effects of IICR, and to determine HF induced changes in ROS dependent IICR regulation and their consequences for atrial remodeling, alternans and atrial fibrillation (AF) risk. The 3 specific aims are: Specific aim 1: Define the mechanism of IP3R co-regulation by IP3 and ROS and determine its sex-specific attributes. We will test the hypotheses that IICR is co-regulated by IP3 and ROS in a defined NOX2/ROS/IP3R microdomain and that ROS dependent glutathionylation of IP3R modulates atrial Ca release during ECC. Alternative candidates of cellular ROS sources (mitochondria, NOX4) for IP3R modulation in addition to NOX2, and sex-specific attributes of ROS/IP3 co-regulation of IICR will be determined. Specific aim 2: Determine atrial remodeling of NOX2/ROS/IP3R signaling and its consequences for ECC, Ca release and transcription factor regulation in HF. We will test the hypothesis that in atrial tissue of a ventricular HF model ROS sources alternative to NOX2 upregulate IICR and thereby change its contribution to atrial Ca transient (CaT), contraction, and transcription factor (NFAT) activation through nuclear IP3Rs. Specific aim 3: Determine the mechanisms of ROS/IICR mediated increase in Ca alternans propensity and AF susceptibility in normal and HF atrial tissue. We will test the hypotheses that IICR facilitates pacing induced CaT alternans that is further enhanced in HF, and that synergistically ROS/IICR mediated alternans generates a substrate that increases the susceptibility for AF episodes.