Heart disease is the leading cause of mortality in the United States and causes more deaths than all cancers combined. Coronary heart disease (or ischemic heart disease, IHD), the most common type of heart disease, is accompanied by a major decline of local pH in myocardium. However, the mechanisms of pH regulation and the homeostasis of H+ neutralizing buffers, such as HCO3- and Cl- in cardiomyocytes remain incompletely understood, making it difficult to design therapeutic strategies targeting pH regulation. Recently, we have identified and cloned different isoforms of a solute carrier, Slc26a6, from cardiac myocytes. Slc26a6 is the predominant Cl-/HCO3- exchanger in the heart. We demonstrated that Slc26a6 mediates electrogenic Cl-/HCO3- exchange activities in both atrial and ventricular myocytes. Our findings raise the possibility that Slc26a6 may represent the predominant Cl-/HCO3- regulatory mechanism in the heart. We have obtained exciting data to support the critical roles of Slc26a6 in cardiac excitability and contractility. We documented that null deletion of Slc26a6 in mice results in shortened action potentials (APs), sinus bradycardia, fragmented QRS complexes and impaired cardiac function compared to wild type littermates. We have identified and characterized two isoforms of human SLC26A6 in human heart, which are also electrogenic, akin to mouse cardiac Slc26a6. In addition, we recently identified and reported a dynamic beat-to-beat intracellular pH (pHi) regulation system, termed “pHi transients”, which dovetails with the prevailing three known dynamic systems, namely electrical, Ca2+, and mechanical systems. However, critical questions remain unanswered. How do Slc26a6 activities affect not only pHi, but also cardiac AP and contractility? The goal of study is to determine the mechanistic links between the Slc26a6 activities and cardiac AP and contractility. Contributions of Slc26a6-mediated Cl-/HCO3- towards the pHi transients will also be tested. Taken together, we hypothesize that the activities of Slc26a6 on pHi will directly contribute towards intracellular Na+ homeostasis, through Na+/HCO3- cotransporter (NBCe) and Na+/H+ exchanger (NHE), and subsequently regulate intracellular Ca2+ concentration through sarcolemmal Na+- Ca2+ exchanger (NCX). Therefore, ablation of Slc26a6 will result in a reduction in intracellular Na+ and Ca2+ through the actions of NHE/NBCe and NCX, respectively. We further hypothesize that Slc26a6 plays important roles in the dynamic pHi regulation in the heart regulating cardiac pacemaking activities and contractility. We will test our hypothesis using multidisciplinary approaches including functional electrophysiological recordings, imaging, biochemical, molecular and genetic approaches as well as ex vivo and in vivo functional studies. Wild type and cardiac-specific Slc26a6 knockout mouse model as well as human cardiomyocytes will be tested. Three specific aims are: 1. To determine the regulatory mechan...