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Original Article |
slipsiu{at}lumc.edu
In atrial myocytes, an initial exposure to isoproterenol (ISO) acts via cAMP to mediate a subsequent acetylcholine (ACh)-induced activation of ATP-sensitive K+ current (IK,ATP). In addition, β-adrenergic receptor (β-AR) stimulation activates nitric oxide (NO) release. The present study determined whether the conditioning effect of β-AR stimulation acts via β1- and/or β2-ARs and whether it is mediated via NO signaling. 0.1 µM ISO plus ICI 118,551 (ISO-β1-AR stimulation) or ISO plus atenolol (ISO-β2-AR stimulation) both increased L-type Ca2+ current (ICa,L) markedly, but only ISO-β2-AR stimulation mediated ACh-induced activation of IK,ATP. 1 µM zinterol (β2-AR agonist) also increased ICa,L and mediated ACh-activated IK,ATP. Inhibition of NO synthase (10 µM L-NIO), guanylate cyclase (10 µM ODQ), or cAMP-PKA (50 µM Rp-cAMPs) attenuated zinterol-induced stimulation of ICa,L and abolished ACh-activated IK,ATP. Spermine-NO (100 µM; an NO donor) mimicked β2-AR stimulation, and its effects were abolished by Rp-cAMPs. Intracellular dialysis of 20 µM protein kinase inhibitory peptide (PKI) abolished zinterol-induced stimulation of ICa,L. Measurements of intracellular NO ([NO]i) using the fluorescent indicator DAF-2 showed that ISO-β2-AR stimulation or zinterol increased [NO]i. L-NIO (10 µM) blocked ISO- and zinterol-induced increases in [NO]i. ISO-β1-AR stimulation failed to increase [NO]i. Inhibition of Gi-protein by pertussis toxin significantly inhibited zinterol-mediated increases in [NO]i. Wortmannin (0.2 µM) or LY294002 (10 µM), inhibitors of phosphatidylinositol 3'-kinase (PI-3K), abolished the effects of zinterol to both mediate ACh-activated IK,ATP and stimulate [NO]i. We conclude that both β1- and β2-ARs stimulate cAMP. β2-ARs act via two signaling pathways to stimulate cAMP, one of which is mediated via Gi-protein and PI-3K coupled to NO-cGMP signaling. Only β2-ARs acting exclusively via NO signaling mediate ACh-induced activation of IK,ATP. NO signaling also contributes to β2-AR stimulation of ICa,L. The differential effects of β1- and β2-ARs can be explained by the coupling of these two β-ARs to different effector signaling pathways.
Key Words: electrophysiology • ion channels • cardiac • PI-3K signaling • G-protein–coupled receptor
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