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

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.

Grant Number: 5R01HL155762-04
NIH Institute/Center: NIH
Principal Investigator: Kathrin Banach