© 1997 American Heart Association, Inc.
Articles |
Phosphatase-Mediated Enhancement of Cardiac cAMP-Activated Cl- Conductance by a Cl- Channel Blocker, Anthracene-9-Carboxylate
From the Department of Cellular and Molecular Physiology (S.-S.Z., M.T., Y.O.), National Institute for Physiological Sciences, Okazaki, Japan, and the Department of Physiology (A.T.), School of Medicine, Nagoya (Japan) University.
Correspondence to Y. Okada, MD, PhD, Department of Cellular and Molecular Physiology, National Institute for Physiological Sciences, Okazaki 444, Japan. E-mail okada{at}nips.ac.jp
Abstract An aromatic carboxylate, anthracene-9-carboxylic
acid (9-AC), is known as a Cl- channel blocker. However,
variable 9-AC effects have hitherto been reported on the cardiac
cAMP-activated Cl- conductance, when applied
extracellularly. We have reexamined the 9-AC effect on the
Cl- conductance activated by isoproterenol or
forskolin in guinea pig ventricular myocytes under
whole-cell patch-clamp conditions. The inward current was blocked by
9-AC at 
0.5 mmol/L, but in contrast, the outward current was
enhanced at much lower concentrations (ED50, 
13
µmol/L). 9-AC applied by the intracellular perfusion technique
increased both the inward and outward currents. In the presence of
intracellular 9-AC, deactivation of the conductance after washout of
isoproterenol or forskolin was largely prevented. 9-AC produced an
enhancing effect, even after inhibiting the deactivation process by
okadaic acid (OA), whereas it failed to produce additional effects in
the presence of orthovanadate. Intracellular application of 9-AC
together with OA virtually abolished the current deactivation. The 9-AC
effects on the Cl- conductance were not dependent on
intracellular Ca2+ or pH. Putative inhibitors
of alkaline (bromotetramisole) and acid phosphatases (tartrate) were
without effect. 9-AC failed to inhibit the activities of purified
protein phosphatase (PP)-1, -2A, and -2C. In the extract of guinea pig
ventricle, 9-AC (10 µmol/L for full action) significantly
inhibited a fraction of endogenous phosphatase activity
that was sensitive to orthovanadate but not to OA, bromotetramisole,
and tartrate. It is concluded that 9-AC blocks cardiac
cAMP-activated (cystic fibrosis transmembrane conductance
regulator) Cl- conductance from the extracellular side but
enhances the conductance from the intracellular side by inhibiting an
orthovanadate-sensitive phosphatase distinct from PP-1, -2A, -2B, or
-2C and alkaline or acid phosphatase.
Key Words: anion channel • cystic fibrosis transmembrane conductance regulator • Cl- channel blocker • dephosphorylation • cardiac myocyte
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