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        Cardiovascular disease is the leading cause of death in Western Societies. When the heart fails to beat in a coordinated, rhythmic fashion death occurs. When blood vessels fail to deliver sufficient blood flow, cell and tissue death occur. Central to coordinated function of both the heart and blood vessels are gap junctions, which provide a selectively permeable pathway for intercellular exchange of the signaling molecules necessary for coordinated function. The selective permeability of gap junctions is determined over long time frames (hours to days and weeks) by their protein composition and over short time frames (seconds to minutes) by protein kinases and phosphatases. We use electrophysiologic tools in combination with fluorescence imaging and molecular tools to address the mechanisms underlying short- and long-term regulation of gap junction function. Our ultimate goal is to understand the role gap junctions play in the physiologic and pathophysiologic function of the heart and blood vessels such that new therapies for the treatment of heart disease can be developed.

        Long-term regulation typically involves changes in the protein composition of the junction. Gap junctions are clusters of intercellular channels each composed of 12 connexin (Cx) subunits, six contributed by each cell. Of the twenty or more connexin genes in the genome, 4 are commonly expressed in cells of the cardiovascular system: Cx45, Cx37, Cx40, and Cx43 (numbers correspond to the predicted molecular weight of the proteins in kilodaltons). Each of these connexins forms channels with distinct selective permeability; Cx43 channels are the least selective, Cx37 or Cx45 the most selective. Most cells express multiple connexin types; the functional impact of co-expression on selective permeability is largely unexplored and a focus of current study in our laboratory. Since the pattern of co-expressed connexins changes during development and in response to disease and injury, our studies should provide new insights into the functional consequences of altered connexin expression in diseases of the cardiovascular system.

        Short-term regulation of cellular functions generally occurs through post-translational modification of proteins that involve kinases and phosphatases. We demonstrated that the conductance of Cx43-composed junctions is regulated by protein kinase C (PKC), Src, and MAPK. We further determined that the effect of PKC requires serine 368 and involves a change in the configuration of the channel evident from reduced unitary conductance. In recent work we have demonstrated that Cx40 channels are not similarly regulated. Through site-directed mutagenesis and electrophysiologic studies we hope to identify which signaling cascade elements target gap junction proteins, how these cascades modify the channel’s function, and determine whether such alterations of function are necessary for normal, coordinated function of blood vessels and the heart.