On the mechanism of rectification of the isoproterenol-activated chloride current in guinea-pig ventricular myocytes.

Overholt, Jeffrey L.; Hobert, Michael E.; Harvey, Robert D.

doi:10.1085/jgp.102.5.871

Cited by 45 publications

(30 citation statements)

References 41 publications

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“…The characteristics of the macroscopic Ic, induced by PMA in guinea-pig ventricular myocytes are quite consistent with those of PKA-activated ICI previously described for these myocytes (cf. Harvey & Hume, 1989;Overholt et al, 1993;Gadsby et al, 1995 (Cooper et al, 1995). In support, there was no elevation of cyclic AMP in rat ventricular myocytes treated with PMA (Lacerda et al, 1988).…”

Section: Indications Of Ca2"-dependent Pkc Involvementmentioning

confidence: 82%

“…Our preliminary data from experiments on I-substitution of external Cl-(-6 mV shift in Erev) suggest PI-1.2Pc1, a value in good accord with the 1.4 Pc1 determined by Walsh & Long (1994) from myocytes dialysed with PKCoc. The P1/Pc1 of cardiac PKA-activated Clchannels is not fully resolved (see Gadsby et al, 1995), with values ranging from 1.67 (Vandenberg et al, 1994) to 0.88 (Overholt et al, 1993).…”

Section: Anion-dependencementioning

confidence: 99%

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Phorbol ester activation of chloride current in guinea‐pig ventricular myocytes

Shuba

Asai

McDonald

1996

British J Pharmacology

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1 Although earlier studies with phorbol esters indicate that protein kinase C (PKC) may be an important regulator of Cl-current (Icl) in cardiac cells, there is a need for additional quantitative data and investigation of conflicting findings. Our objectives were to measure the magnitude, time course, and concentration-dependence of Ic, activated in guinea-pig ventricular myocytes by phorbol 12-myristate 13-acetate (PMA), evaluate its PKC dependence, and examine its modification by external and internal ions. 2 The whole-cell patch clamp technique was used to apply short depolarizing and hyperpolarizing pulses to myocytes superfused with Na+-, K+-, Ca2+-free solution (36°C) and dialysed with Cs' solution. Stimulation of membrane currents by PMA (threshold < I M, EC50s 14 nM, maximal 40% increase with > 100 nM) plateaued within 6 -10 min. 3 PMA-activated current was time-independent, and suppressed by 1 mM 9-anthracenecarboxylic acid (9-AC). Its reversal potential (Erev) was sensitive to changes in the Cl-gradient, and outward rectification of the current-voltage (I-J) relationship was more pronounced with 30 mM than 140 mM Cl-dialysate. 4 The relative permeability of PMA-activated channels estimated from Frev measurements was I-> Cl > > aspartate. Channel activation was independent of external Na+.5 PMA failed to activate Ic, in myocytes pretreated with 1-(5-isoquinolinesulphonyl)-2-methylpiperazine (H-7) or dialysed with pCa 10.5 solution. Lack of response to 4cc-phorbol 12, 13-didecanoate (aPDD) was a further indication of mediation by PKC. 6 I1c induced by 2 giM forskolin was far larger than that induced by PMA, suggesting that endogenous protein kinase A is a much stronger Cl-channel activator than endogenous PKC in these myocytes. 7 The macroscopic properties of PMA-induced I1c appear to be indistinguishable from those of PKAactivated Ics. We discount stimulation of PKA by PMA as an explanation, and conclude that endogenous PKC may activate PKA-regulated Cl-channels in these myocytes.

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Section: Indications Of Ca2"-dependent Pkc Involvementmentioning

confidence: 82%

Section: Anion-dependencementioning

confidence: 99%

Phorbol ester activation of chloride current in guinea‐pig ventricular myocytes

Shuba

Asai

McDonald

1996

British J Pharmacology

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“…Because the cardiac isoform of the cystic fibrosis transmembrane conductance regulator is expressed in ventricular myocytes (27,58), this raises the possibility that genistein-sensitive I Cl,cAMP might contribute to the genistein-sensitive current. Cardiac I Cl,cAMP is, however, a time-independent current at all voltages (28,43); it exhibits a linear I-V relationship in symmetrical high-Cl Ϫ solutions (2,34), and it is insensitive to tamoxifen (50 (47,61). In addition, the biophysical characteristics of the genistein-and PP2-induced currents are inconsistent with I Cl,Ca .…”

Section: Discussionmentioning

confidence: 98%

Antagonistic regulation of swelling-activated Cl⁻current in rabbit ventricle by Src and EGFR protein tyrosine kinases

Ren

Baumgarten²

2005

American Journal of Physiology-Heart and Circulatory Physiology

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Ϫ current (ICl,swell) is complex, and multiple signaling cascades are implicated. To determine whether protein tyrosine kinase (PTK) modulates ICl,swell and to identify the PTK involved, we studied the effects of a broad-spectrum PTK inhibitor (genistein), selective inhibitors of Src (PP2, a pyrazolopyrimidine) and epidermal growth factor receptor (EGFR) kinase (PD-153035), and a protein tyrosine phosphatase (PTP) inhibitor (orthovanadate). I Cl,swell evoked by hyposmotic swelling was increased 181 Ϯ 17% by 100 M genistein, and the genistein-induced current was blocked by the selective ICl,swell blocker tamoxifen (10 M). Block of Src with PP2 (10 M) stimulated tamoxifen-sensitive ICl,swell by 234 Ϯ 27%, mimicking genistein, whereas the inactive analog of PP2, PP3 (10 M), had no effect. Moreover, block of PTP by orthovanadate (1 mM) inhibited ICl,swell and prevented its stimulation by PP2. In contrast with block of Src, block of EGFR kinase with PD-153035 (20 nM) inhibited ICl,swell. Several lines of evidence argue that the PP2-stimulated current was ICl,swell: 1) the stimulation was volume dependent, 2) the current was blocked by tamoxifen, 3) the current outwardly rectified with both symmetrical and physiological Cl Ϫ gradients, and 4) the current reversed near the Cl Ϫ equilibrium potential. To rule out contributions of other currents, Cd 2ϩ (0.2 mM) and Ba 2ϩ(1 mM) were added to the bath. Surprisingly, Cd 2ϩ suppressed the decay of ICl,swell, and Cd 2ϩ plus Ba 2ϩ eliminated time-dependent currents between Ϫ100 and ϩ100 mV. Nevertheless, these divalent ions did not eliminate ICl,swell or prevent its stimulation by PP2. The results indicate that tyrosine phosphorylation controls ICl,swell, and regulation of ICl,swell by the Src and EGFR kinase families of PTK is antagonistic.volume-sensitive Cl Ϫ current; AG 1879; PD-153035; orthovanadate; tamoxifen; genistein; epidermal growth factor receptor OSMOTIC SWELLING OR HYDROSTATIC inflation of cardiac myocytes and numerous other tissues evokes the volume-sensitive Cl Ϫ current I Cl,swell . This current is outwardly rectifying, partially inactivated at positive voltages, and blocked by tamoxifen. These biophysical and pharmacological characteristics distinguish I Cl,swell from other Cl Ϫ currents (for reviews, see Refs. 4 and 28). Under isosmotic conditions, I Cl,swell contributes to the background Cl Ϫ current (17, 18) and is activated in models of cardiac disease (12) and by stretching ␤ 1 -integrins (7, 8).Functionally, the activation of I Cl,swell influences both cardiac electrical activity (16,30,49) and cell volume (11,12).The signaling that underlies the activation of I Cl,swell is complex, and evidence implicates protein kinases C and A and protein tyrosine kinase (PTK) in its regulation in the heart (4, 28) and other tissues (32). PTK is activated by osmotic swelling of myocytes within 5 s (37, 38) and therefore is well positioned to be an early step in the signaling process. Although substantial evidence indicates that phosphorylation and dephosphorylation o...

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“…The behaviour of current reversal in different experimental solutions makes it likely that the most significant charge carrier of 'TI is Cl-. This finding has been also supported by the blocking effect of the known Cl-channel blocker, anthracene-9-carboxylic acid (Hwang & Gadsby, 1994 (Lipp & Niggli, 1994) (Franciolini & Nonner, 1987;Overholt, Hobert & Harvey, 1993), and therefore the possibility of incomplete channel selectivity cannot be excluded. In a recent study (Kawano et al 1995), poor Cl-selectivity of the [Ca2+]i-activated transient outward current has also been observed in rabbit ventricular myocytes.…”

Section: Cell Isolationmentioning

confidence: 94%

Calcium‐activated transient membrane currents are carried mainly by chloride ions in isolated atrial, ventricular and Purkinje cells of rabbit heart

Szigeti

Rusznák

Kovács

et al. 1998

Experimental Physiology

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SUMMARYUnder physiological conditions, calcium-dependent ([Ca2+] -dependent) Cl-currents (ICI(Ca)) have been suggested to participate in the repolarizing processes. In this paper, the possible contribution of ICl(Ca) to transient inward currents and, hence to arrhythmias, has been studied in myocytes from the working myocardium and from the conductive system. Single atrial, ventricular and Purkinje cells, isolated enzymatically from rabbit heart, have been studied under whole-cell voltage-clamp and were internally perfused with the fluorescent Ca2+ indicator, fura-2 (100 /sM). Ca + release from the sarcoplasmic reticulum was either induced by external application of caffeine or occurred spontaneously in Ca2+-overloaded cells. Membrane currents accompanying Ca2+ transients showed linear current-voltage characteristics between -60 and +80 mV as evidenced from fast voltage ramps. When intra-and extracellular Cl-concentrations were kept symmetrical in the absence of the Na+-Ca2' exchange mechanism, transient currents had a reversal potential close to 0 mV.

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On the mechanism of rectification of the isoproterenol-activated chloride current in guinea-pig ventricular myocytes.

Cited by 45 publications

References 41 publications

Phorbol ester activation of chloride current in guinea‐pig ventricular myocytes

Phorbol ester activation of chloride current in guinea‐pig ventricular myocytes

Antagonistic regulation of swelling-activated Cl⁻current in rabbit ventricle by Src and EGFR protein tyrosine kinases

Calcium‐activated transient membrane currents are carried mainly by chloride ions in isolated atrial, ventricular and Purkinje cells of rabbit heart

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On the mechanism of rectification of the isoproterenol-activated chloride current in guinea-pig ventricular myocytes.

Cited by 45 publications

References 41 publications

Phorbol ester activation of chloride current in guinea‐pig ventricular myocytes

Phorbol ester activation of chloride current in guinea‐pig ventricular myocytes

Antagonistic regulation of swelling-activated Cl−current in rabbit ventricle by Src and EGFR protein tyrosine kinases

Calcium‐activated transient membrane currents are carried mainly by chloride ions in isolated atrial, ventricular and Purkinje cells of rabbit heart

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Antagonistic regulation of swelling-activated Cl⁻current in rabbit ventricle by Src and EGFR protein tyrosine kinases