Autonomic Regulation of a Chloride Current in Heart

Harvey, Robert D.; Hume, Joseph R.

doi:10.1126/science.2543073

Cited by 244 publications

(185 citation statements)

References 37 publications

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“…For example it appears that DIDs does not inhibit the adenosine 3':5'-cyclic monophosphate (cyclic AMP)-mediated chloride current in cystic fibrosis airway epithelia (Anderson & Welsh, 1991). In cardiac myocytes, 100gM SITS and DIDS actually enhanced the isoprenaline-induced chloride current which is also mediated by cyclic AMP (Harvey, 1993) although this conductance is sensitive to A-9-C (Harvey & Hume, 1989). In contrast, the voltage-gated chloride conductance in rat cultured astrocytes is significantly inhibited by low concentrations of DIDS (20 f.M) but is insensitive to A-9-C (Gray & Ritchie, 1986).…”

Section: Discussionmentioning

confidence: 99%

Effects of Cl channel blockers on Ca‐activated chloride and potassium currents in smooth muscle cells from rabbit portal vein

Hogg

Wang

Large

1994

British J Pharmacology

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1 The effects of some chloride channel antagonists were studied on the calcium-activated chloride current (ICl(ca)) in smooth muscle cells from the rabbit portal vein with the perforated patch technique.2 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulphonic acid (SITS) and 4,4'-diisothiocyanato-stilbene-2,2'-disulphonic acid (DIDS) reduced the amplitude of spontaneous transient inward currents (STICs, calcium-activated 5 DIDS and SITS decreased the amplitude of IC1(ca) evoked by noradrenaline and caffeine less potently than STICs with IC50 values of 7.5 x 10-4 M and 1.8 x 10-3 M, respectively. 6 DIDS and SITS increased the calcium-activated potassium current (IK(C)) evoked by noradrenaline and caffeine by 3-6 fold. 7 Anthracene-9-carboxylic acid (A-9-C) inhibited STICs in a voltage-dependent fashion and was about 3 fold more active at + 50 mV than at -50 mV. A-9-C increased STIC r and this effect was enhanced by depolarization.8 A-9-C also inhibited caffeine-evoked IC1(ca) but less potently than STICs and also increased the evoked IK(ca) without altering spontaneous IK(Ca). 9 The results from the present work are compared with the pharmacology of other chloride conductances and the mechanism of action of the chloride channel antagonists in vascular smooth muscle is discussed.

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Section: Discussionmentioning

confidence: 99%

Effects of Cl channel blockers on Ca‐activated chloride and potassium currents in smooth muscle cells from rabbit portal vein

Hogg

Wang

Large

1994

British J Pharmacology

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“…The role of anions in cardiac electrophysiology received far less attention as physiological and pharmacological research has focused mainly on cation channels [1] until the discovery of the cAMPactivated Cl − current [2,3]. Anion currents are still less understood regarding their molecular identity, physiological role and biophysical, pharmacological properties [4,5].…”

Section: Introductionmentioning

confidence: 99%

Sarcolemmal Ca 2+ -entry through L-type Ca 2+ channels controls the profile of Ca 2+ -activated Cl − current in canine ventricular myocytes

Horváth

Váczi

Hegyi

et al. 2016

Journal of Molecular and Cellular Cardiology

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Highlights• Ca 2+ -entry via I Ca,L is essential for the activation of I Cl(Ca) • I Cl(Ca) can be activated even in the absence of CICR• TMEM16A and Bestrophin-3 are expressed on human left ventricular muscle• TMEM16A and Bestrophin-3 co-localize with each other and with Ca v 1.2 channels (I Cl(Ca) ) mediated by TMEM16A and/or Bestrophin-3 may contribute to cardiac arrhythmias. The true profile of I Cl(Ca) during an actual ventricular action potential (AP), however, is poorly understood. We aimed to study the profile of I Cl(Ca) systematically under physiological conditions (normal Ca 2+ cycling and AP voltage-clamp) as well as in conditions designed to change [Ca 2+ ] i . The expression of TMEM16A and/or Bestrophin-3 in canine and human left ventricular myocytes was examined. The possible spatial distribution of these proteins and their co-localization with Ca v 1.2 was also studied. The profile of I Cl(Ca), identified as a 9-anthracene carboxylic acid-sensitive current under AP voltageclamp conditions, contained an early fast outward and a late inward component, overlapping early and terminal repolarizations, respectively. Both components were moderately reduced by ryanodine, while fully abolished by BAPTA, but not EGTA. [Ca 2+ ] i was monitored using Fura-2-AM. Setting [Ca 2+ ] i to the systolic level measured in the bulk cytoplasm (1.1 µM) decreased I Cl(Ca), while application of Bay K8644, isoproterenol, and faster stimulation rates increased the amplitude of I Cl(Ca) . Ca 2+ -entry through L-type Ca 2+ channels was essential for activation of I Cl(Ca) . TMEM16A and Bestrophin-3 showed strong co-localization with one another and also with Ca v 1.2 channels, when assessed using immunolabeling and confocal microscopy in both canine myocytes and human ventricular myocardium. Activation of I Cl(Ca) in canine ventricular cells requires Ca 2+ -entry through neighboring L-type Ca 2+ channels and is only augmented by SR Ca 2+ -release. Substantial activation of I Cl(Ca) requires high Ca 2+ in the dyadic clefts which can be effectively buffered by BAPTA, but not EGTA.

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“…In the myocardium, ~-adrenergic agonists regulate a variety of ionic currents (for reviews, see Hartzell, 1988;Gadsby, 1990), including a CI-current identified recently in guinea pig and rabbit ventricular myocytes (Harvey and Hume, 1989;Bahinski, Nairn, Greengard, and Gadsby, 1989b;Matsuoka, Ehara, and Noma, 1990). Activation of that CI-conductance requires phosphorylation by cAMP-dependent protein kinase (PKA) because the CI-conductance can be elicited by direct intracellular application of either cAMP or the catalytic subunit of PKA (Bahinski et al, 1989b), and it can be abolished (Bahinski, Gadsby, Greengard, and Nairn, 1989a;Hwang, Horie, Nairn, and Gadsby, 1992c) by intracellular application of a specific peptide inhibitor of PKA (PKI; i.e., Walsh inhibitor, 5-24-amide; Cheng, Kemp, Pearson, Smith, Misconi, Van Patten, and Walsh, 1986).…”

Section: Introductionmentioning

confidence: 99%

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

Hwang

Horie

Gadsby

1993

The Journal of General Physiology

107

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The regulation of cardiac CI-conductance by cAMP-dependent protein kinase (PKA) and cellular phosphatases was studied in isolated guinea pig ventricular myocytes by using wide-tipped, perfused pipettes to record whole-cell currents. Exposure to forskolin (Fsk) or isoproterenol (Iso) elicits a CI-conductance that results exclusively from PKA-dependent phosphorylation because it can be completely abolished, or its activation fully prevented, by switching to pipette solution containing PKI, a synthetic peptide inhibitor of PKA. The CI-conductance activated by micromolar concentrations of either agonist reached its steady-state amplitude in 1-2 min and was deactivated promptly and entirely, usually within 2 min, upon washing out the agonist, implying a continuous high level of activity of endogenous protein phosphatases. Accordingly, intraceUular application of okadaic acid or microcystin, both potent inhibitors of protein phosphatases 1 and 2A, during exposure to Fsk enhanced the steady-state CI-conductance and slowed its deactivation after washing out the Fsk. Maximal potentiation of the conductance, by ~ 60%, was obtained with pipette concentrations of ~ 10 I~M okadaic acid (or ~ 5 ~tM microcystin) and did not result from an increase in the apparent affirfity for Fsk. In the presence of maximally effective concentrations of okadaic acid and/or microcystin, deactivation of the enhanced CI-conductance upon washout of agonist was incomplete, with about half of the conductance persisting indefinitely. That residual conductance did not reflect continued action of PKA because it was insensitive to PKI, but was identified as a fraction of the activated CI-conductance by its biophysical characteristics. The results suggest that complete deactivation of the PKA-regulated cardiac CI-conductance requires dephosphorylation by a type 1 and/or 2A phosphatase, but that partial deactivation can be accomplished by activity of some other phosphatase(s). These findings are' consistent with sequential phosphorylation of a protein, probably the CI-channel itself, at two different kinds

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Autonomic Regulation of a Chloride Current in Heart

Cited by 244 publications

References 37 publications

Effects of Cl channel blockers on Ca‐activated chloride and potassium currents in smooth muscle cells from rabbit portal vein

Effects of Cl channel blockers on Ca‐activated chloride and potassium currents in smooth muscle cells from rabbit portal vein

Sarcolemmal Ca 2+ -entry through L-type Ca 2+ channels controls the profile of Ca 2+ -activated Cl − current in canine ventricular myocytes

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

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