Phosphatase-mediated enhancement of cardiac cAMP-activated Cl-conductance by a Cl- channel blocker, anthracene-9-carboxylate.

doi:10.1161/01.RES.81.2.219

Paper

Phosphatase-mediated enhancement of cardiac cAMP-activated Cl-conductance by a Cl- channel blocker, anthracene-9-carboxylate.

Published Aug 1, 1997 · S. S. Zhou, A. Takai, M. Tominaga

Circulation research

Q1 SJR score

22

Citations

0

Influential Citations

Full textSemantic Scholar

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 > or = 0.5 mmol/L, but in contrast, the outward current was enhanced at much lower concentrations (ED50, approximately 13 mumol/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 (> or = 10 mumol/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.

In Vitro Study

Study Snapshot

Anthracene-9-carboxylic acid (9-AC) blocks cardiac cAMP-activated Cl-conductance extracellularly but enhances it intracellularly by inhibiting a distinct phosphatase distinct from PP-1, -2A, -2B, or -2C.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Sign up to use Study Snapshot

Consensus is limited without an account. Create an account or sign in to get more searches and use the Study Snapshot.

Create an account

Paper

Phosphatase-mediated enhancement of cardiac cAMP-activated Cl-conductance by a Cl- channel blocker, anthracene-9-carboxylate.

Sign up to use Study Snapshot

References

Distribution of cAMP-activated chloride current and CFTR mRNA in the guinea pig heart.

Regional differences in CFTR mRNA expression in the guinea pig heart partially explain the regional differences in cAMP-activated chloride current density.

Cystic fibrosis gene encodes a cAMP-dependent chloride channel in heart.

The CFTR gene encodes a cAMP-dependent chloride channel in the heart, which plays a crucial role in autonomic regulation of action potential duration and membrane potential.

CFTR chloride channels in human and simian heart.

CFTR chloride channels are molecularly expressed and functionally expressed in human and simian hearts, with both exon 5 plus and exon 5 minus transcripts co-expressed.

Glibenclamide, an ATP-sensitive K+ channel blocker, inhibits cardiac cAMP-activated Cl- conductance.

Glibenclamide inhibits cardiac cAMP-activated Cl- conductance, potentially affecting heart rate and blood pressure in patients with type 2 diabetes.

Swelling-activated and isoprenaline-activated chloride currents in guinea pig cardiac myocytes have distinct electrophysiology and pharmacology

Guinea pig cardiac myocytes express swelling-activated chloride channels in atrial cells and isoprenaline-activated chloride channels in ventricular cells, suggesting coordinated regulation of different Cl- channel expression within the heart.

Phosphatase inhibitors activate normal and defective CFTR chloride channels.

Phosphatase inhibitors can activate both normal and defective CFTR chloride channels, suggesting they could be a potential therapeutic target for treating cystic fibrosis.

Coupling of CFTR Cl− channel gating to an ATP hydrolysis cycle

CFTR channel opening and closing are linked to an ATP hydrolysis cycle, with VO4 and BeF3 analogs increasing their mean open time by 2-3 orders of magnitude.

Single‐channel study of the cyclic AMP‐regulated chloride current in guinea‐pig ventricular myocytes.

Cyclic AMP system makes 'latent' chloride channels available without influencing their own kinetic behavior, and these channels may intrinsically exhibit a high open probability.

Functionally distinct phospho-forms underlie incremental activation of protein kinase-regulated Cl- conductance in mammalian heart

PKA-regulated cardiac Cl- conductance is regulated by two distinct phosphoproteins, with complete deactivation requiring type 1 and/or 2A phosphatase dephosphorylation, but partial deactivation can be accomplished by other phosphatase(s).

Citations

Cell Volume-Activated and Volume-Correlated Anion Channels in Mammalian Cells: Their Biophysical, Molecular, and Pharmacological Properties

Volume-activated anion channels (VAACs) and volume-correlated anion channels (VCACs) play distinct roles in cell volume changes, and future studies are needed for therapeutic targeting of their dysfunction.

Mechanism of allosteric activation of TMEM16A/ANO1 channels by a commonly used chloride channel blocker

Anthracene-9-carboxylic acid (A9C) can both activate and inhibit calcium-activated chloride channels, offering potential therapeutic targets for conditions like asthma and hypertension.

Multiple effects of anthracene-9-carboxylic acid on the TMEM16B/anoctamin2 calcium-activated chloride channel.

Anthracene-9-carboxylic acid (A9C) has multiple effects on the TMEM16B calcium-activated chloride channel, with its negative charge being necessary for both voltage-dependent block and potentiation.

Coordination Tendency of N-Acetylamino Acids, Nucleotides, and DNA Toward the Luminescent Bioprobes Tb(III)-Bathophenanthroline or Tb(III)-Anthracene-9-Carboxylic Acid

N-acetylamino acids, nucleotides, and DNA show strong coordination tendencies towards the luminescent bioprobes Tb(III)-Bathophenanthroline or Tb(III)-Anthracene-9-Carboxylic Acid, indicating potential

Effects of monocarboxylic acid‐derived Cl− channel blockers on depolarization‐activated potassium currents in rat ventricular myocytes

Monocarboxylic acid-derived calcium channel blockers NPPB and NFA enhance cardiac steady-state potassium current, likely through stimulation of PKA and PTK signaling pathways.