Voltage‐dependent and calcium‐dependent inactivation of calcium channel current in identified snail neurones.

Gutnick, Michael J.; Lux, H. D.; Swandulla, Dieter; Zucker, Howard D.

doi:10.1113/jphysiol.1989.sp017611

Cited by 99 publications

(88 citation statements)

References 56 publications

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“…An alternative pathway that may account for the Ca 2ϩ -dependent inactivation of Ca 2ϩ channels is the direct interaction of Ca 2ϩ ions with the channel protein. 34,46 Such a direct binding of Ca 2ϩ ions has been proposed by Gutnick et al 17 for molluscan Ca 2ϩ channels. de Leon et al 11 and Imredy and Yue 23 have recently provided evidence for such a direct effect on native and artificially expressed cardiac L-type Ca 2ϩ channels, and similar mechanisms may also exist in neuronal Land N-type Ca 2ϩ channels.…”

Section: Discussionmentioning

confidence: 75%

Calcium-dependent inactivation of neuronal calcium channel currents is independent of calcineurin

Zeilhofer¹,

Blank

Neuhuber

et al. 1999

Neuroscience

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Abstract-Dephosphorylation by the Ca 2ϩ /calmodulin-dependent phosphatase calcineurin has been suggested as an important mechanism of Ca 2ϩ -dependent inactivation of voltage-gated Ca 2ϩ channels. We have tested whether calcineurin plays a role in the inactivation process of two types of high-voltage-activated Ca 2ϩ channels (L and N type) widely expressed in the central nervous system, using the immunosuppressive drug FK506 (tacrolimus), which inhibits calcineurin after binding to intracellular FK506 binding proteins. Inactivation of L-and N-type Ca 2ϩ channels was studied in a rat pituitary tumor cell line (GH 3 ) and chicken dorsal root ganglion neurons, respectively. With the use of antisera directed against the calcineurin subunit B and the 12,000 mol. wt binding protein, we show that both proteins are present in the cytoplasm of GH 3 cells and chicken dorsal root ganglion neurons. Ionic currents through voltage-gated Ca 2ϩ channels were investigated in the perforated-patch and whole-cell configurations of the patch-clamp technique. The inactivation of L-as well as N-type Ca 2ϩ currents could be well fitted with a bi-exponential function. Inactivation was largely reduced when Ba 2ϩ substituted for extracellular Ca 2ϩ or when the Ca 2ϩ chelator EGTA was present intracellularly, indicating that both types of Ca 2ϩ currents exhibited Ca 2ϩ -dependent inactivation. Extracellular (perforated-patch configuration) or intracellular (whole-cell configuration) application of FK506 to inactivate calcineurin had no effect on the amplitude and time-course of Ca 2ϩ channel current inactivation of either L-or N-type Ca 2ϩ channels. In addition, we found that recovery from inactivation and rundown of N-type Ca 2ϩ channel currents were not affected by FK506.Our results provide direct evidence that the calcium-dependent enzyme calcineurin is not involved in the inactivation process of the two Ca 2ϩ channel types which are important for neuronal functioning, such as gene expression and transmitter release. ᭧ 1999 IBRO. Published by Elsevier Science Ltd.Key words: Ca 2ϩ channel, inactivation, calcineurin, FK506, FKBP.An increase in the intracellular concentration of free Ca 2ϩ ([Ca 2ϩ ] i ) plays a pivotal role in a large variety of physiological functions, such as excitation-secretion coupling and neuronal plasticity. On the other hand, excessive increases in [Ca 2ϩ ] i may lead to excitotoxic cell death, which occurs, for example, during brain ischemia and epileptic seizures. 16 In neurons, one important pathway that leads to an increase in [Ca 2ϩ ] i is the opening of voltage-gated Ca 2ϩ channels in the plasma membrane. The activity of these Ca 2ϩ channels is effectively regulated by G-protein-coupled receptors and by Ca 2ϩ -and voltage-dependent inactivation of these ion channels. 3,13,40 Among the different types of Ca 2ϩ channels, Ca 2ϩ -dependent inactivation is best documented for L-type Ca 2ϩ channels. 2,23,24,34,46 However, a Ca 2ϩ -mediated component of Ca 2ϩ channel inactivation has also been described for N-typ...

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Section: Discussionmentioning

confidence: 75%

Calcium-dependent inactivation of neuronal calcium channel currents is independent of calcineurin

Zeilhofer¹,

Blank

Neuhuber

et al. 1999

Neuroscience

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“…The ability of 10 mM EGTA to suppress the Ca-dependent component of inactivation we have observed suggests that the site of Ca 2+ action may be some distance away from the channel protein as the extent to which EGTA effectively buffer intracellular Ca 2+ declines precipitously within tens of nanometers of the channel pore (Gutnick, Lux, Swandulla, and Zucker, 1989). For the Ca 2+ current of Helix neurons an enzymatic mechanism of Ca-dependent inactivation has been suggested whereby dephosphorylation of the channels by a Ca-dependent phosphatase causes channel inactivation (Chad and Eckert, 1986).…”

Section: Discussionmentioning

confidence: 98%

“…In addition to in a variety of invertebrate systems (Brehm and Eckert, 1978;Tillotson, 1979;Ashcroft and Stanfield, 1981;Eckert and Chad, 1984;Gutnick et al, 1989;Johnson and Byerly, 1993), Ca2+-dependent inactivation has been described for L-type Ca 2+ channels of mammalian cardiac muscle and neurohypophysis (Kass and Sanguinetti, 1984;Bechem and Pott, 1985;Kalman et al, 1988;Yue, Backx, and Imredy, 1990). Negative feedback control of Ca 2+ entry may be a common mechanism for the regulation of intracellular Ca z+ levels.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of N-type calcium current in chick sensory neurons: calcium and voltage dependence.

Cox

Dunlap

1994

The Journal of General Physiology

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We have studied the inactivation of high-voltage-activated (HVA), t0-conotoxin-sensitive, N-type Ca 2+ current in embryonic chick dorsal root ganglion (DRG) neurons. Voltage steps from -80 to 0 mV produced inward Ca ~+ currents that inactivated in a biphasic manner and were fit well with the sum of two exponentials (with time constants of ~ 100 ms and > 1 s). As reported previously, upon depolarization of the holding potential to -40 mV, N current amplitude was significantly reduced and the rapid phase of inactivation all but eliminated (Nowycky, M. C., A. P. Fox, and R. W. be explained by a model in which N channels inactivate by both fast and slow voltage-dependent processes. Alternatively, kinetic models of Ca-dependent inactivation suggest that the biphasic kinetics and holding-potential-dependence of N current inactivation could be due to a combination of Ca-dependent and slow voltage-dependent inactivation mechanisms. To distinguish between these possibilities we have performed several experiments to test for the presence of Cadependent inactivation. Three lines of evidence suggest that N channels inactivate in a Ca-dependent manner. (a) The total extent of inactivation increased 50%, and the ratio of rapid to slow inactivation increased ~ twofold when the concentration of the Ca 2 § buffer, EGTA, in the patch pipette was reduced from 10 to 0.1 mM. (b) With low intracellular EGTA concentrations (0.1 mM), the ratio of rapid to slow inactivation was additionally increased when the extracellular Ca 2 § concentration was raised from 0.5 to 5 mM. (c) Substituting Na § for Ca 2 § as the permeant ion eliminated the rapid phase of inactivation. Other results do not support the notion of current-dependent inactivation, however. Although high intraceUular EGTA (10

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“…Inhibition of recovery from inactivation by C a 2ϩ has been seen in a number of other preparations (Brehm et al, 1980;Yatani et al, 1983;Gutnick et al, 1989). More detailed kinetic studies of Ca 2ϩ channel inactivation have been undertaken by others to explain a large body of data (Gutnick et al, 1989;Mazzanti et al, 1991;Fryer and Zucker, 1993;Imredy and Yue, 1994). The comparatively simple two-state analysis used here is presented solely to clarify two apparently conflicting results of increased rate of inactivation and reduced steady-state level of inactivation.…”

Section: ؉ -Dependent Inactivationmentioning

confidence: 99%

Ca²⁺- and Voltage-Dependent Inactivation of Ca²⁺Channels in Nerve Terminals of the Neurohypophysis

1997

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Ca2ϩ channel inactivation was investigated in neurohypophysial nerve terminals by using patch-clamp techniques. ]. However, this contribution was small compared to that of voltage. In contrast to voltage-gated Ca 2ϩ channels in other preparations, in the neurohypophysis Ba 2ϩ substitution or intracellular BAPTA increased the speed of inactivation while reducing the steady-state level of inactivation. Ca 2ϩ channel recovery from inactivation was studied by using a paired-pulse protocol. The rate of Ca 2ϩ channel recovery from inactivation at negative potentials was increased dramatically by Ba 2ϩ substitution or intracellular BAPTA, indicating that intracellular Ca 2ϩ inhibits recovery. Stimulation with trains of brief pulses designed to mimic physiological bursts of electrical activity showed that Ca 2ϩ channel inactivation was much greater with 20 Hz trains than with 14 Hz trains. Inactivation induced by 20 Hz trains was reduced by intracellular BAPTA, suggesting an important role for Ca 2ϩ -dependent inactivation during physiologically relevant forms of electrical activity. Inhibitors of calmodulin and calcineurin had no effect on Ca 2ϩ channel inactivation, arguing against a mechanism of inactivation involving these Ca 2ϩ -dependent proteins. The inactivation behavior described here, in which voltage effects on Ca 2ϩ channel inactivation predominate at positive potentials and Ca 2ϩ effects predominate at negative potentials, may be relevant to the regulation of neuropeptide release.

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Voltage‐dependent and calcium‐dependent inactivation of calcium channel current in identified snail neurones.

Cited by 99 publications

References 56 publications

Calcium-dependent inactivation of neuronal calcium channel currents is independent of calcineurin

Calcium-dependent inactivation of neuronal calcium channel currents is independent of calcineurin

Inactivation of N-type calcium current in chick sensory neurons: calcium and voltage dependence.

Ca²⁺- and Voltage-Dependent Inactivation of Ca²⁺Channels in Nerve Terminals of the Neurohypophysis

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Voltage‐dependent and calcium‐dependent inactivation of calcium channel current in identified snail neurones.

Cited by 99 publications

References 56 publications

Calcium-dependent inactivation of neuronal calcium channel currents is independent of calcineurin

Calcium-dependent inactivation of neuronal calcium channel currents is independent of calcineurin

Inactivation of N-type calcium current in chick sensory neurons: calcium and voltage dependence.

Ca2+- and Voltage-Dependent Inactivation of Ca2+Channels in Nerve Terminals of the Neurohypophysis

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Ca²⁺- and Voltage-Dependent Inactivation of Ca²⁺Channels in Nerve Terminals of the Neurohypophysis