Delayed Rectifier Currents in Rat Globus Pallidus Neurons Are Attributable to Kv2.1 and Kv3.1/3.2 K⁺Channels

Abstract

The symptoms of Parkinson disease are thought to result in part from increased burst activity in globus pallidus neurons. To gain a better understanding of the factors governing this activity, we studied delayed rectifier K(+) conductances in acutely isolated rat globus pallidus (GP) neurons, using whole-cell voltage-clamp and single-cell RT-PCR techniques. From a holding potential of -40 mV, depolarizing voltage steps in identified GP neurons evoked slowly inactivating K(+) currents. Analysis of the tail currents revealed rapidly and slowly deactivating currents of similar amplitude. The fast component of the current deactivated with a time constant of 11. 1 +/- 0.8 msec at -40 mV and was blocked by micromolar concentrations of 4-AP and TEA (K(D) approximately 140 microM). The slow component of the current deactivated with a time constant of 89 +/- 10 microseconds at -40 mV and was less sensitive to TEA (K(D) = 0.8 mM) and 4-AP (K(D) approximately 6 mM). Organic antagonists of Kv1 family channels had little or no effect on somatic currents. These properties are consistent with the hypothesis that the rapidly deactivating current is attributable to Kv3.1/3.2 channels and the slowly deactivating current to Kv2.1-containing channels. Semiquantitative single-cell RT-PCR analysis of Kv3 and Kv2 family mRNAs supported this conclusion. An alteration in the balance of these two channel types could underlie the emergence of burst firing after dopamine-depleting lesions.

HCN2 and HCN1 Channels Govern the Regularity of Autonomous Pacemaking and Synaptic Resetting in Globus Pallidus Neurons

“…These relative densities were used to estimate the ability of GABAergic synaptic events to activate each channel type. A more complete model of GP neuron spiking was constructed by adding channels known to be important to the spiking of GP neurons; mod files for Na ϩ , Kv1, Kv2, Kv3, Kv4, and Kv7 (KNCQ) channels were constrained by experimental data (Baranauskas et al, 1999;Tkatch et al, 2000;Baranauskas et al, 2003) and incorporated. These mod files are available on request.…”

“…In some experiments, neurons were aspirated after whole-cell recording in the slice for mRNA profiling. Because of incomplete mRNA harvesting with this approach, in another set of experiments GP neurons were acutely dissociated using procedures similar to those that we have described previously (Baranauskas et al, 1999). Acutely isolated neurons were aspirated into sterilized glass pipettes containing nominally RNase-free patch solution or diethylpyrocarbonate-treated water and 0.8 U/l SUPERase-In (Ambion, Austin, TX).…”

“…In an attempt to provide a better mechanistic understanding of this phenomenon, simulations were performed with a model that included key conductances known to regulate pacemaking in GP neurons (Baranauskas et al, 1999;Tkatch et al, 2000;Baranauskas et al, 2003). The model accurately reproduced the experimentally observed membrane potential trajectory of GP neurons and autonomous pacemaking in the 10 -15 Hz range.…”

Differential Regulation of Action Potential Shape and Burst-Frequency Firing by BK and Kv2 Channels in Substantia Nigra Dopaminergic Neurons

“…However, all of these potassium currents are slowly gating, and none are likely to be the dominant potassium currents controlling rapid repolarization of spikes within bursts. In addition to helping control frequency of firing within bursts, such potassium currents are likely to help control entry into the state of depolarization block, to which dopamine neurons appear particularly susceptible (Grace and Bunney, 1986;Grace et al, 1997;Blythe et al, 2009;Qian et al, 2014).…”

Activity-dependent Phosphorylation of Neuronal Kv2.1 Potassium Channels by CDK5

“…Kv2.1, a delayed rectifier-type voltage-gated potassium or Kv channel expressed in high density clusters in somatodendritic domains of mammalian neurons (1)(2)(3), is subjected to rapid activity-dependent, calcineurin-dependent dephosphorylation, resulting in a more hyperpolarized threshold for activation of Kv2.1 currents and loss of clustering (4 -12) and leading to homeostatic suppression of neuronal firing (6,13). Removal of these stimuli leads to recovery of Kv2.1 phosphorylation and clustering (5,7,9,10,12).…”