PHYSIOLOGY OF CARDIAC GAP JUNCTIONS

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Gap junctions from different tissues show considerable diversity in structural and functional properties. However, it has not yet been determined whether the functional differences can be localized to specific structural domains of the proteins. Moreover, the physiological significance of this diversity remains unknown. The goal of this project is to determine the relation between structure and function of gap junctions in the heart and other tissues. A detailed understanding of gap junctions operate is essential to our overall understanding of the role gap junction play under both normal and pathological conditions. For the next grant period there are three specific aims: 1. To express cloned mammalian and amphibian gap junctional proteins in a Xenopus occyte expression system and study their gating properties. Using pairs of Xenopus oocytes which have been injected with mRNA for the cloned proteins, I will study changes in junctional conductance in response to agents that may either directly or indirectly modify junctional conductance (e.g. calcium, protons, phorbol esters, cAMP, transjunctional voltage or transmembrane voltage, local anesthetics.) 2. To alter the structure of gap junctions in order to localize functional properties of the channels to specific domains within the proteins. Once a functional property has been localized to a specific domain, I plan to use site directed mutagenesis to identify which amino acids are involved in the process. 3. To characterize gap junctional conductance (Gj) from cell pairs isolated from adult canine atrial muscle.