Phosphatidylinositol-bisphosphate regulates intercellular coupling in cardiac myocytes
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Changes in the lipid composition of cardiac myocytes have been reported during cardiac hypertrophy, cardiomyopathy, and infarction. Because a recent study indicates a relation between low phosphatidylinositol-bisphosphate (PIP(2)) levels and reduced intercellular coupling, we tested the hypothesis that agonist-induced changes in PIP(2) can result in a reduction of the functional coupling of cardiomyocytes and, consequently, in changes in conduction velocity. Intercellular coupling was measured by Lucifer Yellow dye transfer in cultured neonatal rat cardiomyocytes. Conduction velocity was measured in cardiomyocytes grown on microelectrode arrays. Intercellular coupling was reduced by angiotensin II (43.7 +/- 9.3%, N = 11) and noradrenaline (58.0 +/- 10.7%, N = 11). To test if reduced intercellular coupling after agonist stimulation was caused by PIP(2)-depletion, myocytes were stimulated by angiotensin II (57.3 +/- 5.7%, N = 14) and then allowed to recover in medium with or without wortmannin (an inhibitor of PIP(2) synthesis). Intercellular coupling fully recovered in control medium (102.1 +/- 8.9%, N = 10), whereas no recovery occurred in the presence of wortmannin (69.3 +/- 7.8%, N = 12). Inhibition of PKC, calmodulin, or arachidonic acid production did not affect the response to either angiotensin II or noradrenaline. Furthermore, decreasing or increasing PIP(2) also decreased and increased intercellular coupling, respectively. This supports the role of PIP(2) in the regulation of intercellular coupling. In beating myocytes, conduction velocity was reduced by angiotensin II stimulation, and recovery after wash out was prevented by inhibition of PIP(2) production. Reductions in PIP(2) inhibit intercellular coupling in cardiomyocytes, and stimulation by physiologically relevant agonists reduces intercellular coupling by this mechanism. The reduction in intercellular coupling lowered conduction velocity.
|Journal||Pflügers Archiv: European Journal of Physiology|
|Number of pages||10|
|Publication status||Published - 2008|
Keywords: Androstadienes; Angiotensin II; Animals; Animals, Newborn; Arachidonic Acid; Calcium; Cell Communication; Cells, Cultured; Dose-Response Relationship, Drug; GTP-Binding Protein alpha Subunits, Gq-G11; Gap Junctions; Myocardial Contraction; Myocytes, Cardiac; Norepinephrine; Phosphatidylinositol Phosphates; Protein Kinase C; Protein Kinase Inhibitors; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptors, Adrenergic, beta-1; Signal Transduction; Time Factors