Noradrenaline up‐regulates volume‐regulated chloride current by PKA‐independent cAMP/exchange protein activated by cAMP pathway in human atrial myocytes

Background and Purpose Adrenergic regulation of cell volume‐regulated chloride current (I Cl.vol ) is species‐dependent. The present study investigates the mechanism underlying adrenergic regulation of I Cl.vol in human atrial myocytes. Experimental Approach Conventional whole‐cell patch voltage‐clamp techniques were used to record membrane current in human atrial myocytes. I Cl.vol was evoked by hyposmotic bath solution (0.6 times isosmotic, 0.6 T). Key Results I Cl.vol was augmented by noradrenaline (1 μM) during cell swelling in 0.6 T but not under isosmotic (1 T) conditions. Up‐regulation of I Cl.vol in 0.6 T was blocked by the β‐adrenoceptor antagonist propranolol (2 μM), but not by the α 1 ‐adrenoceptor antagonist prazosin (2 μM). This β‐adrenergic response involved cAMP but was independent of PKA; the protein kinase inhibitor H‐89 (2 μM) or PKI (10 μM in pipette solution) failed to prevent I Cl.vol up‐regulation by noradrenaline. Moreover, the PI3K/PKB inhibitor LY294002 (50 μM) and the PKG inhibitor KT5823 (10 μM) did not affect noradrenaline‐induced increases in I Cl.vol . Interestingly, the exchange protein directly activated by cAMP (Epac) agonist 8‐pCPT‐2′‐O‐Me‐cAMP (50 μM) also up‐regulated I Cl.vol , and the noradrenaline‐induced increase of I Cl.vol in 0.6 T was reversed or prevented by the Epac inhibitor ESI‐09 (10 μM). Conclusion and Implications These data show that I Cl.vol evoked by cell swelling of human atrial myocytes is up‐regulated by noradrenaline via a PKA‐independent cAMP/Epac pathway in human atrial myocytes. cAMP/Epac‐induced I Cl.vol is expected to shorten action potential duration during human atrial myocytes swelling and may be involved in abnormal cardiac electrical activity during cardiac pathologies that evoke β‐adrenoceptor signalling.