**Acknowledgements**

**Orai Orai SAN-dependent**

**Arrhythmogenic Signaling Pathway**

cation occurs but the lower open box notes four possibilities we are now investigating

**Ca**

four possibilities we are now investigating.

**10. Conclusions**

rectly enhance muscle excitability.

**Ca Ca**

114 Atrial Fibrillation - Mechanisms and Treatment

**action potentials**

**Ca Protein complex rearrangement**

**Figure <sup>17</sup>**: **Potential Cellular Mechanism for Orai Atypical Automaticity**. Our preliminary data favor <sup>a</sup> mechanism for Orai atypical automaticity in which calcium entry activates a signaling pathway that modifies the properties of the voltage-dependent ion channels critical to myocyte excitation. We do not have a preferred view as to how this modification occurs but the lower open box notes

Atrial (*and ventricular*) arrhythmias are disturbances in electrical activity that disrupt the regular, rhythmic contraction of the upper (*or lower*) heart chambers. These electrical insta‐ bilities arise from normal or dysfunctional heart muscle, from the heart specialized conduc‐ tion system or from the 'muscular sleeves' of major supraventricular vessels. Because arrhythmia is recorded as abnormal electrical activity and since experimental faradic stimu‐ lation can initiate arrhythmia, it is viewed as having a purely electrical origin. Indeed the dominant explanations for arrhythmia hypothesize it originates from (a) changes in the elec‐ trical properties of heart muscle that alter electrical impulse conduction, (b) changes in the properties of the voltage-dependent ion channels responsible for normal electrical activity which alter impulse conduction, (c) changes in the myocytic milieu that permit normal volt‐ age-dependent ion channels to spontaneously generate electrical impulses or (d) changes in myocyte calcium homeostasis that alter heart resting membrane potential or otherwise indi‐

During the past fifty years, however, it has become clear that all cells contain a staggering array of interrelated signaling pathways and processes which regulate normal and 'abnor‐ mal' cell functions. Like all other cells, heart cells, too, express voltage-independent calcium signaling pathways which underlie cardiac processes like inotropy and diseases like hyper‐ trophy or atherosclerosis. The three earlier hypotheses for arrhythmia noted above ignore

**Figure 17. Potential Cellular Mechanism for Orai Atypical Automaticity.** Our preliminary data favor a mechanism for Orai atypical automaticity in which calcium entry activates a signaling pathway that modifies the properties of the voltage-dependent ion channels critical to myocyte excitation. We do not have a preferred view as to how this modifi‐

**Myocyte-driven action potentials**

**Protein complex assembly (e.g. caveolae) Specific protein-protein interaction Post-translation modification**

**Focal ectopy**

> The authors gratefully acknowledge the help of Dr. Pei Pei Wang in conducting the per‐ fused heart studies described here. PEW appreciatively thanks Dr. David D. Ku of the UAB Department of Pharmacology for unfettered access to lab space and equipment during the course of much of this work. PEW thanks Dr. Jian Huang of the UAB Department of Medi‐ cine for performing microelectrode measurements of left atrial action potential mentioned in the text. He also gratefully acknowledges the assistance of Drs. Hernan E. Grenett, Edlue Ta‐ bengwa, and John C. Chatham of UAB at various points along this journey. He also would like to thank Dr. Neal Kay of UAB for his interest in this endeavor. PEW is the President and Chief Scientific Officer of KOR Therapies, LLC which seeks to develop the technology dis‐ cussed in this paper. This technology is now controlled by the University of Alabama Re‐ search Foundation and under patent review.
