Fine Gating Properties of Channels Responsible for Persistent Sodium Current Generation in Entorhinal Cortex Neurons

Magistretti , Jacopo; Alonso , Angel

doi:10.1085/jgp.20028676

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Article| November 11 2002

Fine Gating Properties of Channels Responsible for Persistent Sodium Current Generation in Entorhinal Cortex Neurons

Jacopo Magistretti,

Jacopo Magistretti

1Department of Neurology and Neurosurgery, McGill University and Montreal Neurological Institute, Montréal, Québec H3A 2B4, Canada

2Dipartimento di Scienze Fisiologiche-Farmacologiche Cellulari-Molecolari, Università degli Studi di Pavia, 27100 Pavia, Italy

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Angel Alonso

1Department of Neurology and Neurosurgery, McGill University and Montreal Neurological Institute, Montréal, Québec H3A 2B4, Canada

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Author and Article Information

Jacopo Magistretti

1Department of Neurology and Neurosurgery, McGill University and Montreal Neurological Institute, Montréal, Québec H3A 2B4, Canada

2Dipartimento di Scienze Fisiologiche-Farmacologiche Cellulari-Molecolari, Università degli Studi di Pavia, 27100 Pavia, Italy

Angel Alonso

1Department of Neurology and Neurosurgery, McGill University and Montreal Neurological Institute, Montréal, Québec H3A 2B4, Canada

Address correspondence to Dr. Jacopo Magistretti, Dipartimento di Scienze Fisiologiche-Faramacologiche, Cellulari-Molecolari Sezione di Fisiologia Generale e Biofisica Cellulare, Università degli Studi di Pavia, Via Forlanini 6, 27100 Pavia, Italy. Fax: (39) 0382-507527; E-mail: [email protected]

*

Abbreviations used in this paper: CNS, central nervous system; EC, entorhinal cortex; PHR, parahippocampal region.

¹

Events <100 μs (the sampling interval of the long-lasting depolarizing protocols here applied) were missed in our dwell-time analysis. This limitation could affect our estimations of mean open and closed times. The algorithms that can be employed to correct such errors (e.g., Colquhoun and Sigworth, 1983) could not be applied here, since the fastest time constants observed (see Table I) were not long enough as compared to the limit of resolution of the measurements, which is one of the basic requirements for these corrections being applicable. Therefore, the time constants we report are uncorrected, and should be interpreted as upper bonds for the exact, real values.

²

In this case, if two channels opening with equal probability were responsible for the persistent activity observed, ∼5% of the opening time would be predicted to consist of superimposed openings. However, the possibility that multiple channels, each opening sporadically, generated single bursts in these patches, although unlikely, cannot be unequivocally ruled out. As a consequence, our estimation of mean interburst closed time (τ_c(slow)) should be taken as a lower limit for true value(s). It is also worth to note that, if the τ_c(slow) value we provide is underestimated, the criterion we used to discriminate between intra- and interburst closings (see the first paragraph of results) would be even safer.

³

Again, we stress that in the present context the expression “NaP channels” is used for brevity and does not necessarily imply the existence of a specific population of Na⁺ channels exclusively devoted to persistent Na⁺ current generation. It is simply meant to indicate those channels the openings of which produce the “persistent” Na⁺ channel activity here studied and underlie the macroscopic I_NaP.

⁴

It is worth noting that τ_b0 was prominently represented also in the initial phases of 20-s depolarizing pulses, although to a lesser extent than in later phases, whereas it was virtually absent, even in the same patches, when 500-s depolarizing pulses delivered from −100 mV were considered (see above). This explains the much shorter

\(\overline{\mathrm{{\tau}}}_{\mathrm{b}}\)

values found in the initial phases of 20-s traces as compared to those observed in 500-ms protocols. The reason for this discrepancy could be that repetitive, long-lasting depolarizing pulses induce a “short-lived” bursting behavior, and that full recovery from this process requires longer repolarizations than the inter-episode time (20 s) that separated the single 20-s pulses in the protocol we applied.

Received: July 18 2002

Revision Received: September 17 2002

Accepted: October 15 2002

Online ISSN: 1540-7748

Print ISSN: 0022-1295

The Rockefeller University Press

2002

J Gen Physiol (2002) 120 (6): 855–873.

https://doi.org/10.1085/jgp.20028676

The gating properties of channels responsible for the generation of persistent Na⁺ current (I_NaP) in entorhinal cortex layer II principal neurons were investigated by performing cell-attached, patch-clamp experiments in acutely isolated cells. Voltage-gated Na⁺-channel activity was routinely elicited by applying 500-ms depolarizing test pulses positive to −60 mV from a holding potential of −100 mV. The channel activity underlying I_NaP consisted of prolonged and frequently delayed bursts during which repetitive openings were separated by short closings. The mean duration of openings within bursts was strongly voltage dependent, and increased by e times per every ∼12 mV of depolarization. On the other hand, intraburst closed times showed no major voltage dependence. The mean duration of burst events was also relatively voltage insensitive. The analysis of burst-duration frequency distribution returned two major, relatively voltage-independent time constants of ∼28 and ∼190 ms. The probability of burst openings to occur also appeared largely voltage independent. Because of the above “persistent” Na⁺-channel properties, the voltage dependence of the conductance underlying whole-cell I_NaP turned out to be largely the consequence of the pronounced voltage dependence of intraburst open times. On the other hand, some kinetic properties of the macroscopic I_NaP, and in particular the fast and intermediate I_NaP-decay components observed during step depolarizations, were found to largely reflect mean burst duration of the underlying channel openings. A further I_NaP decay process, namely slow inactivation, was paralleled instead by a progressive increase of interburst closed times during the application of long-lasting (i.e., 20 s) depolarizing pulses. In addition, long-lasting depolarizations also promoted a channel gating modality characterized by shorter burst durations than normally seen using 500-ms test pulses, with a predominant burst-duration time constant of ∼5–6 ms. The above data, therefore, provide a detailed picture of the single-channel bases of I_NaP voltage-dependent and kinetic properties in entorhinal cortex layer II neurons.

The Rockefeller University Press

2002

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