α₁-Adrenergic activation of myocardial Na-K-2Cl cotransport involving mitogen-activated protein kinase

Abstract

The translocation mechanisms involved in the α1-adrenoceptor-stimulated efflux of the potassium analog86Rb+were studied in isolated rat hearts. Phenylephrine (in the presence of a β-blocker) increased the efflux of86Rb+and42K+, and the Na-K-2Cl (or K-Cl) cotransport inhibitor bumetanide reduced the response by 42 ± 11%. Furosemide inhibited the response with a lower potency than that of bumetanide. The bumetanide-insensitive efflux was largely sensitive to the K+ channel inhibitor 4-aminopyridine. Inhibitors of the Na+/H+exchanger or the Na+-K+pump had no effect on the increased86Rb+efflux. The activation of the Na-K-2Cl cotransporter was dependent on the extracellular signal-regulated kinase (ERK) subgroup of the mitogen-activated protein (MAP) kinase family. Phenylephrine stimulation increased ERK activity 3.4-fold. PD-98059, an inhibitor of the ERK cascade, reduced both the increased86Rb+efflux and ERK activity. Specific inhibitors of protein kinase C and Ca2+/calmodulin-dependent kinase II had no effect. In conclusion, α1-adrenoceptor stimulation increases86Rb+efflux from the rat heart via K+channels and a Na-K-2Cl cotransporter. Activation of the Na-K-2Cl cotransporter is apparently dependent on the MAP kinase pathway.

Duality of G protein-coupled mechanisms for β-adrenergic activation of NKCC activity in skeletal muscle

“…In addition, it has been shown that stimulation of NKCC activity is MAPK dependent in striated muscle (2,31). The present study demonstrates that ␤-AR stimulation can activate fiber phenotype-specific signaling cascades that involve both G s -and G i -coupled processes.…”

H2O2-induced Ca2+overload in NRVM involves ERK1/2 MAP kinases: role for an NHE-1-dependent pathway

“…This suggests that ERK1/2 can regulate other ion transporters independently of NHE-1. The possible targets for ERK1/2 that could contribute to the cytosolic Na ϩ and Ca 2ϩ load include the Na ϩ -K ϩ -2Cl Ϫ cotransporter, which is activated by ␣ 1 -adrenergic agonist in an ERK1/2-dependent mechanism in cardiac myocytes (2), or the Na ϩ -HCO 3 Ϫ cotransporter, which is coupled to muscarinic receptor activation by ERK1/2 in renal epithelial cells (30). We cannot rule out the possibility that ERK1/2 can directly modulate NCX or Na ϩ /K ϩ pump activity that could also contribute to alterations in Ca 2ϩ or Na ϩ homeostasis.…”

α1-AR-mediated activation of NKCC in rat cardiomyocytes involves ERK-dependent phosphorylation of the cotransporter

“…Hearts from deeply ether-anesthetized adult male Wistar rats (200-250 g) were excised and placed into ice-cold saline. The hearts were retrogradely aorta perfused as described in detail previously (3). The hearts were spontaneously beating and perfused in a nonrecirculating system at 31°C and at a constant flow of 10 ml/min.…”

“…The presence of a myocardial NKCC was suggested early by the findings of loop diuretic-sensitive ion transport (mainly K ϩ or the potassium analog 86 Rb ϩ ) in heart preparations from different species (8,12,14,21). A more extensive characterization of myocardial Na-K-2Cl cotransport is lacking, but we have previously reported that both ␣ 1 -adrenoceptor (AR) and angiotensin II receptor stimulation activated bumetanide-sensitive 86 Rb ϩ efflux in perfused rat hearts (2,3). We found that ␣ 1 -AR-induced activation of bumetanide-sensitive 86 Rb ϩ efflux was blocked by a specific inhibitor of MAPK kinase (MAPKK or MEK1) activation, suggesting that the bumetanide-sensitive 86 Rb ϩ efflux is regulated by an extracellular signal-regulated protein kinase (ERK)-dependent pathway (3).…”

“…A more extensive characterization of myocardial Na-K-2Cl cotransport is lacking, but we have previously reported that both ␣ 1 -adrenoceptor (AR) and angiotensin II receptor stimulation activated bumetanide-sensitive 86 Rb ϩ efflux in perfused rat hearts (2,3). We found that ␣ 1 -AR-induced activation of bumetanide-sensitive 86 Rb ϩ efflux was blocked by a specific inhibitor of MAPK kinase (MAPKK or MEK1) activation, suggesting that the bumetanide-sensitive 86 Rb ϩ efflux is regulated by an extracellular signal-regulated protein kinase (ERK)-dependent pathway (3). These studies were not cell specific and could involve noncardiomyocytes as well as cardiomyocytes.…”