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Cast & Stage
B Simms
X Zhan
H Asmara
G Sahu
A Rizwan
S Dykstra
J Miclat
B King
NC Heath
A Kim
D Anderson
T Bartoletti
H Mehaffey
M Iftinca
ML Molineux
F Fernandez
BE McKay
N Lemon
K Luykenaar
J. Bau
T Seredynski
R Tadayon-
G Zamponi
P Stys

Citations in the Faculty of 1000


Fernandez, F.R.*, Mehaffey, W.H.*, Molineux, M.L. and Turner, R.W. (2005) High threshold K+ current increases gain by offsetting a frequency-dependent increase in low threshold K+ current. J. Neuroscience 25(2): 363-371. * Shared first author. PDF Faculty of 1000 citation.

Reviewer: L. Maler, University of Ottawa, Canada
Date: Jan 26, 2005
Recommended [6]
This paper demonstrates that different types of potassium channels present in the same cell can have complex interactions that permit high frequency firing. Two potassium currents, high threshold (HT) and low threshold currents (LT) are commonly co-expressed in fast firing cells. The authors show that the HT current has its effect almost exclusively in the high frequency firing range of the cell, consistent with extensive evidence that these channels are important for high frequency firing. Previous theories have suggested that this effect may be due to the HT currents preventing Na+ current inactivation, and this effect is confirmed in this paper. The slower LT currents are important in controlling excitability and enhancing signal to noise ratio; however, these currents would be expected to temporally summate and therefore dampen excitability and prevent high frequency firing. The authors have demonstrated that, by hyperpolarizing the membrane, the HT channels act to prevent the buildup of LT currents, thus permitting high frequency firing. This work suggests that different families of potassium channels have interactions among themselves that are as complex as the more thoroughly analyzed interactions with sodium channels. Acting together, they appear to be able to control excitability over a very large firing range.

Fernandez, F.R., Engbers, J.D.T. and Turner, R.W. (2007) Firing dynamics of cerebellar Purkinje cells. J. Neurophysiology 98(1): 278-94. PDF    Faculty of 1000 citation.

Reviewer: E. deSchutter, University of Antwerp, Belgium
Date: May 31, 2007
Recommended [6]
       This article presents a dynamical system analysis of simple spike firing in cerebellar Purkinje cells, combining simple models with experimental analysis, and advances our understanding of the mechanisms underlying bistability in these neurons.
       In addition, the paper refutes previous simple models which tried to explain this phenomenon. Specifically, the bistability is between a rest state and a firing state, not between a hyperpolarized and depolarized state, and the Ih current is not essential.

Anderson, D., Mehaffey, W.H., Iftinca, M., Rehak, R., Engbers, J.D.T., Hameed, S., Zamponi, G.W. and Turner, R.W.  (2010) Regulation of neuronal activity by Cav3-Kv4 channel signaling complexes. Nature Neuroscience 13: 333-337. Link   Faculty of 1000 citation.

Reviewer: R. Burgoyne, University of
Liverpool, UK
Date: Feb 18, 2010
Recommended [8]
This article shows that calcium entry through T-type calcium channels can modulate the function of Kv4 A-type potassium channels in cerebellar stellate cells. This occurs through the calcium-binding Kv channel interacting protein (KChIP)3, which is part of a complex containing the two channels. These findings are important as they identify a novel mechanism for the dynamic regulation of neuronal excitability that could be of widespread physiological significance.
       A-type potassium channels have key roles in regulating neuronal firing. The A-type channels formed from Kv4 channel subunits have a number of constitutively associated proteins. These include KChIP1-4, a set of calcium-binding proteins that have been shown to stimulate the traffic of Kv4 channels to the plasma membrane and to modify the gating kinetics of the channels {1}. It had not been known whether calcium-binding to KChIPs could dynamically regulate Kv4 channel function. The authors have studied Kv4 channels in cerebellar stellate cells and also in heterologous expression systems. They found that calcium entry through T-type (Cav3) calcium channels can rapidly and reversibly (within seconds) shift the voltage-dependence of inactivation of the Kv4 channels to more negative membrane potentials. This was shown to modify the excitability of the stellate neurons. The mechanisms underlying this regulation were characterised and found to involve a signalling complex of the Kv4 and Cav3 channels with associated KChIP3 allowing Kv4 regulation by nanodomains of calcium.
Interestingly, KChIPs 1, 2 and 4 were unable to replace KChIP3, consistent with other findings suggesting distinct functional roles for KChIP3 {2}.
       Overall, this paper presents three novel findings. First, that Kv4 channels can be rapidly and dynamically regulated by calcium. Second, that this involves calcium entry through associated T-type channels. Third, that the calcium sensor involved is specifically KChIP3 and not other KChIPs. Since Kv4 and Cav3 channels and KChIP3 are expressed in many neuronal cell types, the identified mechanism could have a general role in regulating neuronal excitability. It would be interesting if the significance of this mechanism was probed more widely including use of existing KChIP3 knock-out mice {3,4}.
NB-I am an author on ref {2} (this is cited as it is the only other study in the literature that shows a specific function for KChIP3 over the other KChIPs as seen in this new study).

Engbers, J.D.T.*, Anderson, D.*, Asmara, H., Rehak, R., Mehaffey, W.H., Hameed, S., McKay, B.E., Kruskic, M., Zamponi, G.W. and Turner, R.W. (2012) Intermediate conductance calcium-activated potassium channels modulate summation of parallel fiber input in cerebellar Purkinje cells. PNAS 109 (7): 2601-2606. * Shared first authors.
Reviewer: N. Dascal, Tel Aviv University, Israel
Date: Jan 15, 2012
Recommended [6]
        Cerebellar Purkinje cells are inhibitory neurons crucially involved in the control of motor performance, and their degeneration or malfunction leads to diseases characterized by ataxia and other motor deficiencies. This paper describes a novel molecular and cellular mechanism of regulation of electrical activity of these cells. The paper is a true tour-de-force, the underlying molecular and cellular mechanism is fascinating, and the physiological implications are important for the understanding of normal physiology and, potentially, pathophysiology of cerebellar function. This paper demonstrates the presence of a molecular complex of a low-threshold (T-type) voltage-dependent calcium channel Cav3.2 with intermediate conductance calcium-dependent K+ channel KCa3.1 in Purkinje neurons. Voltage-dependent calcium entry via Cav3.2 selectively activates KCa3.1, producing afterhyperpolarization (AHP) following action potentials or even single excitatory postsynaptic potentials (EPSPs), exerting an inhibitory control over summation of excitatory inputs to these cells at low frequencies but allowing excitation by high-frequency stimulation. This mechanism is thus suggested to play a role of a high-pass filter of excitatory inputs to Purkinje cells, playing an important role in the regulation of locomotion alongside other, previously described inhibitory mechanisms.
        Substantial pains have been taken to demonstrate the presence of KCa3.1 in these neurons (previously these calcium-dependent K+ channels have been shown in peripheral neurons but not in the central nervous system) and the unique participation of Cav3.2 in the specific activation of KCa3.1. The close apposition of the two channels is suggested by co-immunoprecipitation and by the inability of a slow calcium chelator, ethylene glycol tetraacetic acid (EGTA), to block KCa3.1 activation, whereas the fast calcium chelator BAPTA and a calmodulin inhibitor suppress the action of calcium, suggesting a tight complex of the three proteins (KCa3.1 relies on calmodulin for activation by calcium).
        The high voltage sensitivity of Cav3.2 and its relatively wide window of activation by voltage, potentially allowing activity within a -80mV and -40mV range (the exact temporal and voltage characteristics of this window remain to be better understood), confer unique properties on this inhibitory mechanism. Due to the high sensitivity to voltage and calcium and the tight apposition of the calcium and K+ channels, KCa3.1 is activated already by very small, local influx of calcium via Cav3.2, exerting an inhibitory effect on even a single EPSP, thus crucially reducing the summation of EPSPs and preventing Purkinje cell excitation by low-frequency stimulation. Due to the width of the window of voltages that allow Cav3.2 activity, this mechanism is also operational during trains of action potentials, in line with its proposed high-frequency filter role. It is plausible that regulation of this molecular complex by neurotransmitters via protein phosphorylation or other mechanisms may fine-tune its performance and regulate Purkinje cells' firing. In all, the new regulatory mechanism discovered by Engbers et al. appears to carry out an important role in regulating Purkinje neurons' function. Future molecular studies may reveal the crucial interaction sites between the two channels. A selective disruption of the latter in model animals (e.g. by a point mutation) may provide essential insights into the exact physiological role of this fascinating molecular mechanism.


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