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Noradrenaline up-regulates volume-regulated chloride current by PKA-independent cAMP/exchange protein activated by cAMP pathway in human atrial myocytes.
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ABSTRACT: Background and purpose
Adrenergic regulation of cell volume-regulated chloride current (ICl.vol ) is species-dependent. The present study investigates the mechanism underlying adrenergic regulation of ICl.vol in human atrial myocytes.Experimental approach
Conventional whole-cell patch voltage-clamp techniques were used to record membrane current in human atrial myocytes. ICl.vol was evoked by hyposmotic bath solution (0.6 times isosmotic, 0.6 T).Key results
ICl.vol was augmented by noradrenaline (1 μM) during cell swelling in 0.6 T but not under isosmotic (1 T) conditions. Up-regulation of ICl.vol in 0.6 T was blocked by the β-adrenoceptor antagonist propranolol (2 μM), but not by the α1 -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 ICl.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 ICl.vol . Interestingly, the exchange protein directly activated by cAMP (Epac) agonist 8-pCPT-2'-O-Me-cAMP (50 μM) also up-regulated ICl.vol , and the noradrenaline-induced increase of ICl.vol in 0.6 T was reversed or prevented by the Epac inhibitor ESI-09 (10 μM).Conclusion and implications
These data show that ICl.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 ICl.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.
SUBMITTER: Xiao GS
PROVIDER: S-EPMC6057899 | biostudies-literature | 2018 Aug
REPOSITORIES: biostudies-literature
Publications
Noradrenaline up-regulates volume-regulated chloride current by PKA-independent cAMP/exchange protein activated by cAMP pathway in human atrial myocytes.
British journal of pharmacology 20180708 16
<h4>Background and purpose</h4>Adrenergic regulation of cell volume-regulated chloride current (I<sub>Cl.vol</sub> ) is species-dependent. The present study investigates the mechanism underlying adrenergic regulation of I<sub>Cl.vol</sub> in human atrial myocytes.<h4>Experimental approach</h4>Conventional whole-cell patch voltage-clamp techniques were used to record membrane current in human atrial myocytes. I<sub>Cl.vol</sub> was evoked by hyposmotic bath solution (0.6 times isosmotic, 0.6 T).< ...[more]