Connexins and impulse propagation in the mouse heart

Abstract

Gap junction channels are essential for normal cardiac impulse propagation. Three gap junction proteins, known as connexins, are expressed in the heart: Cx40, Cx43, and Cx45. Each of these proteins forms channels with unique biophysical and electrophysiologic properties, as well as spatial distribution of expression throughout the heart. However, the specific functional role of the individual connexins in normal and abnormal propagation is unknown. The availability of genetically engineered mouse models, together with new developments in optical mapping technology, makes it possible to integrate knowledge about molecular mechanisms of intercellular communication and its regulation with our growing understanding of the microscopic and global dynamics of electrical impulse propagation during normal and abnormal cardiac rhythms. This article reviews knowledge on the mechanisms of cardiac impulse propagation, with particular focus on the role of cardiac connexins in electrical communication between cells. It summarizes results of recent studies on the electrophysiologic consequences of defects in the functional expression of specific gap junction channels in mice lacking either the Cx43 or Cx40 gene. It also reviews data obtained in a transgenic mouse model in which cell loss and remodeling of gap junction distribution leads to increased susceptibility to arrhythmias and sudden cardiac death. Overall, the results demonstrate that these are potentially powerful strategies for studying fundamental mechanisms of cardiac electrical activity and for testing the hypothesis that certain cardiac arrhythmias involve gap junction or other membrane channel dysfunction. These new approaches, which permit one to manipulate electrical wave propagation at the molecular level, should provide new insight into the detailed mechanisms of initiation, maintenance, and termination of cardiac arrhythmias, and may lead to more effective means to treat arrhythmias and prevent sudden cardiac death.