Mechanisms of Na⁺-K⁺pump regulation in cardiac myocytes during hyposmolar swelling

Abstract

We have previously demonstrated that the sarcolemmal Na+-K+pump current ( I p) in cardiac myocytes is stimulated by cell swelling induced by exposure to hyposmolar solutions. However, the underlying mechanism has not been examined. Because cell swelling activates stretch-sensitive ion channels and intracellular messenger pathways, we examined their role in mediating I pstimulation during exposure of rabbit ventricular myocytes to a hyposmolar solution. I p was measured by the whole cell patch-clamp technique. Swelling-induced pump stimulation altered the voltage dependence of I p. Pump stimulation persisted in the absence of extracellular Na+ and under conditions designed to minimize changes in intracellular Ca2+, excluding an indirect influence on I pmediated via fluxes through stretch-activated channels. Pump stimulation was protein kinase C independent. The tyrosine kinase inhibitor tyrphostin A25, the phosphatidylinositol 3-kinase inhibitor LY-294002, and the protein phosphatase-1 and -2A inhibitor okadaic acid abolished I pstimulation. Our findings suggest that swelling-induced pump stimulation involves the activation of tyrosine kinase, phosphatidylinositol 3-kinase, and a serine/threonine protein phosphatase. Activation of this messenger cascade may cause activation by the dephosphorylation of pump units.

Natriuretic peptides stimulate the cardiac sodium pump via NPR-C-coupled NOS activation

“…A dephosphorylation step is implicated in ANP-induced pump stimulation, but the specific step cannot be identified. The sensitivity to OA of pump stimulation induced by other stimuli has been reported previously (4,16).…”

Extracellular Hypotonicity Increases Na,K-ATPase Cell Surface Expression via Enhanced Na+ Influx in Cultured Renal Collecting Duct Cells

“…Exposure of renal amphibian A6 cells, a model of mammalian principal cells, to extracellular hypotonicity was shown to stimulate Na ϩ influx through ENaC (4 -6). Hypotonic cell swelling is associated with a stimulation of the Na ϩ -pump current in both renal A6 cells (7) and cardiac myocytes (8). In addition, hypotonic conditions recruit active Na,K-ATPase units to the cell surface in isolated rabbit cortical CD (CCD) (9).…”

Involvement of the phosphatidylinositol kinase pathway in augmentation of ATP-sensitive K+ channel currents by hypo-osmotic stress in rat ventricular myocytes

“…It was reported that hypo-osmotic cell swelling increased the Cl -channel currents (I Cl ), delayed rectifier K + currents (I Ks ), non-selective cation current, Na-K pump current, and I K,ATP in cardiac myocytes (Sasaki et al 1994;Zhou et al 1997;Priebe and Beuckelmann 1998;Bewick et al 1999;Kocic et al 2001;Kocic et al 2004a;Kocic et al 2004b;Kocic et al 2007;Ren et al 2008;Piron et al 2010). Several mechanisms have been proposed for the hypo-osmotic stimulation of these ionic conductance including the activation of tyrosine kinase, phophatidylinositol 3-kinase (PI-3K) and a serine/threonine protein phosphatase, and the interaction with actin filaments (Zhou et al 1997;;Bewick et al 1999;Kocic et al 2004b;Ren et al 2008;Piron et al 2010).…”

“…Several mechanisms have been proposed for the hypo-osmotic stimulation of these ionic conductance including the activation of tyrosine kinase, phophatidylinositol 3-kinase (PI-3K) and a serine/threonine protein phosphatase, and the interaction with actin filaments (Zhou et al 1997;;Bewick et al 1999;Kocic et al 2004b;Ren et al 2008;Piron et al 2010). For example, it was proposed that in rabbit ventricular myocytes hypo-osmotic swelling activated volume-sensitive Cl -current (I Cl,swell ) by stimulation of angiotensin-II type I receptor, thereby evoking the downstream signaling via tyrosine kinase and PI-3K, causing assembly of NADPH oxidase (Ren et al 2008).…”