Protein kinase A hyperphosphorylation increases basal current but
decreases beta-adrenergic responsiveness of the sarcolemmal Na$^+$-Ca$^2+$
exchanger in failing pig myocytes.
Circ. Res. 92
(8):
897-903 (May 2003)
The sodium-calcium exchanger (NCX) protein is the major cardiac calcium
extrusion mechanism and is upregulated in heart failure (HF). NCX
expression level and functional activity as regulated by beta-adrenergic
receptor (beta-AR) stimulation in swine with and without tachycardia-induced
heart failure were studied. The Ni2+-sensitive NCX current was measured
in myocytes from HF and control animals in the basal state or in
the presence of isoproterenol, forskolin, 8-Br-cAMP, okadaic acid,
or protein phosphatase type 1. Western blot analysis revealed a significant
increase in both the 120-kDa (29\%) and 80-kDa (69\%) fragments in
HF (P<0.05 versus control). Despite this modest increase in protein,
the basal peak outward NCX current was increased almost 5-fold in
HF (P<0.05 versus control). Stimulation with isoproterenol, however,
increased the control currents to a significantly greater extent
than HF (500\% increase in control versus 100\% increase in HF, P<0.01);
peak stimulated current was not different in HF and control. This
reduction in responsiveness to beta-AR stimulation was refractory
to forskolin, 8-Br-cAMP, or okadaic acid stimulation. In vitro
protein kinase A back-phosphorylation revealed higher phosphorylation
capacity of NCX protein in control versus HF, consistent with increased
phosphorylation in vivo (hyperphosphorylation) in HF. Protein phosphatase
type 1 exposure resulted in a significant reduction (73\%) in peak
basal current in HF (compared with no significant difference in controls),
confirming that the increased basal NCX current in HF is predominantly
attributable to hyperphosphorylation. NCX expression and activity
are thus increased in HF, although beta-AR responsiveness is decreased
because of NCX hyperphosphorylation.
Tags
126768188-bromoacid,adenosineadrenergicadrenergic,amp-dependentanimals,beta,beta-agonists,cardiac,cells,congestive,cultured,cyclicexchanger,failure,female,forskolin,gov't,heartisoproterenol,kinases,male,membranemonophosphate,myocardium,myocytes,non-u.s.okadaicp.h.s.,phosphatase,phosphoproteinphosphorylation,potentials,proteinreceptors,researchsarcolemma,sodium-calciumsupport,swine,u.s.
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