Gap junctions are the cell-to-cell channels which permit electrical coupling between cardiac myocytes in the adult heart and facilitate the passage of morphogens between cells in the developing myocardium. Studies proposed are aimed at determining the roles and regulation of gap junction-mediated intercellular communication in the embryology and differentiation of the heart. The embryonic chick heart contains several physiologically distinct gap junctions. It also contains developmentally-regulated mRNAs coding for three different gap junction proteins (connexins) which have been sequenced. Connexin specific antisera will be raised to unique synthetic peptides. Those antisera will be used for immunocytochemical studies to investigate the timing and location of expression of gap junctions composed of each connexin. These studies will determine which cells are coupled by which connexins, which connexins are present in the presumptive and forming myocardium, how and when they form communication compartments, and how the distributions change with cardiac morphogenesis. The physiological regulation of the embryonic cardiac gap junction will be studied by the stable expression of each of the individual connexins from their cloned cDNAs in a cell line which is normally devoid of any gap junctions. In these transfected cells, the biophysical properties of each connexin will be determined, including: (1) unitary channel conductance, (2) existence of temperature dependent sub-conductance states, (3) trans-junctional voltage dependence, and (4) sensitivity to (a) anesthetics, (b) PH, and (c) Ca2+. Modified and hybrid connexins will be expressed in which specific domains have been altered. These experiments will allow us to correlate precisely the molecular structural domains within each connexin with its physiological regulation. These studies will help explain congenital cardiac malformations by elucidating the roles of intercellular communication in cardiac morphogenesis.
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