Distribution and functional significance of the P-type, voltage-dependent Ca2+ channels in the mammalian central nervous system

Llinás, Rodolfó R.; Sugimori, Mutsuyuki; Hillman, Dean E.; Cherksey, Bruce D.

doi:10.1016/0166-2236(92)90053-b

Cited by 307 publications

(128 citation statements)

References 12 publications

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“…Another sustained calcium channel is the P-type calcium channel. 26,39 We did not expect our sustained current to resemble much of this channel type, based on recent single channel measurements. 28 The second component analysed in the HVA current was the transient current.…”

Section: Current Separationmentioning

confidence: 97%

Calcium currents in pyramidal CA1 neurons in vitro after kindling epileptogenesis in the hippocampus of the rat

1996

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Calcium currents in pyramidal CA1 neurons in vitro after kindling epileptogenesis in the hippocampus of the rat Faas, G.C.; Vreugdenhil, M.; Wadman, W.J. Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Abstract--Calcium is an important second messenger which plays a role in the regulation of neuronal excitability and in many forms of synaptic plasticity. In kindling epileptogenesis, a model of focal epilepsy, calcium plays an important role. The in situ patch-clamp technique was used to record calcium currents in slices obtained from kindled rats and controls. We found that low-voltage-activated calcium currents, probably of dendritic origin, were larger after kindling (80%). The transient high-voltage-activated calcium currents were also enhanced after kindling (50% higher). The increase of the current is accompanied by a decrease in the time constant of inactivation. The change was still present six weeks after the kindling stimulations were stopped. These data demonstrate that low-voltage-activated calcium currents are involved in epileptogenesis. Their enhancement in the dendrites will boost synaptic depolarization and result in enhanced calcium influx, which is critically dependent on the specific activation pattern.

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Section: Current Separationmentioning

confidence: 97%

Calcium currents in pyramidal CA1 neurons in vitro after kindling epileptogenesis in the hippocampus of the rat

1996

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“…Ca V 2.1 channels are located in presynaptic terminals throughout the brain (13) and play a prominent role in controlling neurotransmitter release at most synapses (14). Their localization in somatodendritic membranes points to additional postsynaptic roles (15)(16)(17). Studies of mutant Ca V 2.1 channels in heterologous expression systems revealed that FHM mutations alter both the single-channel biophysical properties and the density of functional channels in the membrane (18)(19)(20).…”

mentioning

confidence: 99%

Familial hemiplegic migraine mutations increase Ca ²⁺ influx through single human Ca _V 2.1 channels and decrease maximal Ca _V 2.1 current density in neurons

Tottene

Fellin

Pagnutti

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

232

191

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Insights into the pathogenesis of migraine with aura may be gained from a study of human CaV2.1 channels containing mutations linked to familial hemiplegic migraine (FHM). Here, we extend the previous single-channel analysis to human CaV2.1 channels containing mutation V1457L. This mutation increased the channel open probability by shifting its activation to more negative voltages and reduced both the unitary conductance and the density of functional channels in the membrane. To investigate the possibility of changes in Ca V2.1 function common to all FHM mutations, we calculated the product of single-channel current and open probability as a measure of Ca 2؉ influx through single CaV2.1 channels. All five FHM mutants analyzed showed a single-channel Ca 2؉ influx larger than wild type in a broad voltage range around the threshold of activation. We also expressed the FHM mutants in cerebellar granule cells from CaV2.1␣1 ؊/؊ mice rather than HEK293 cells. The FHM mutations invariably led to a decrease of the maximal CaV2.1 current density in neurons. Current densities were similar to wild type at lower voltages because of the negatively shifted activation of FHM mutants. Our data show that mutational changes of functional channel densities can be different in different cell types, and they uncover two functional effects common to all FHM mutations analyzed: increase of single-channel Ca 2؉ influx and decrease of maximal CaV2.1 current density in neurons. We discuss the relevance of these findings for the pathogenesis of migraine with aura.

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“…The P-type Ca 2+ current displays a high-activation threshold (> -40 mV), almost no inactivation, nanomolar sensitivity to o~Aga-IV A, and micromolar sensitivity to the cone snail peptide ~0CmTx-MVII C. The Q-type Ca z+ current, exhibiting the same voltage range for activation, is poorly inhibited by ~0Aga-IV A but is more sensitive to ¢oCmTx-MVII C ( [1][2][3][4][5], for review [6]). The physiological roles of these P-and Q-type Ca 2+ channels are not yet fully understood, but it has been suggested that both types play a crucial role in the Ca2+-dependent neurotransmitter release in central synapses and at the mammalian neuromuscular junction [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

“…Fax: (33)67-52-15-59. E-maih charnet@Xerxes.crbm.cnrs-mop, fr situ hybridisation and immuno-localisation experiments have shown that the class A ctl subunit is expressed in Purkinje cells [17,18] and at the neuromuscular junction [19], where Ptype Ca 2+ currents are known to be predominant [2,6]. This ctlA subunit, when expressed in Xenopus oocytes, encodes a ¢oCmTx-MVII C-sensitive Ca 2+ channel, closely related to the Q-type Ca ~+ channel described in neurones [3].…”

Section: Introductionmentioning

confidence: 99%

Modulation of the α1A Ca²⁺ channel by β subunits at physiological Ca²⁺ concentration

et al. 1996

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The class A Ca 2+ channel ¢xl snbunit (cdA) was expressed in Xenopus oocytes alone or in combination with the I~lb, l~2a, 113, or I]4 subunit. Analysis of voltage-dependent activation and inactivation in the presence of 1.8 mM external Ca 2+ showed an hyperpolarising shift of both relations when compared to similar recordings performed in the presence of 40 mM Ba 2+. These shifts, which differed for activation and inactivation, were strongly modulated by the nature of the coexpressed ~ subunit. On the other hand, for each combination, the kinetics of inactivation were similar in 1.8 mM Ca 2+ and 40 mM Ba z+ (for example co-expression of the l~2a subuult reduced inactivation using either 40 mM Ba 2+ or 1.8 mM Ca2+). Thus, modulation of channel properties by the ~ subunit is different in physiological Ca 2+ or high Ba 2÷ concentrations. These results must be taken into consideration to extrapolate the role of the subunit in native cells.

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Distribution and functional significance of the P-type, voltage-dependent Ca2+ channels in the mammalian central nervous system

Cited by 307 publications

References 12 publications

Calcium currents in pyramidal CA1 neurons in vitro after kindling epileptogenesis in the hippocampus of the rat

Calcium currents in pyramidal CA1 neurons in vitro after kindling epileptogenesis in the hippocampus of the rat

Familial hemiplegic migraine mutations increase Ca ²⁺ influx through single human Ca _V 2.1 channels and decrease maximal Ca _V 2.1 current density in neurons

Modulation of the α1A Ca²⁺ channel by β subunits at physiological Ca²⁺ concentration

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Distribution and functional significance of the P-type, voltage-dependent Ca2+ channels in the mammalian central nervous system

Cited by 307 publications

References 12 publications

Calcium currents in pyramidal CA1 neurons in vitro after kindling epileptogenesis in the hippocampus of the rat

Calcium currents in pyramidal CA1 neurons in vitro after kindling epileptogenesis in the hippocampus of the rat

Familial hemiplegic migraine mutations increase Ca 2+ influx through single human Ca V 2.1 channels and decrease maximal Ca V 2.1 current density in neurons

Modulation of the α1A Ca2+ channel by β subunits at physiological Ca2+ concentration

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Familial hemiplegic migraine mutations increase Ca ²⁺ influx through single human Ca _V 2.1 channels and decrease maximal Ca _V 2.1 current density in neurons

Modulation of the α1A Ca²⁺ channel by β subunits at physiological Ca²⁺ concentration