A New Kv1.2 Channelopathy Underlying Cerebellar Ataxia

Abstract

A forward genetic screen of mice treated with the mutagen ENU identified a mutant mouse with chronic motor incoordination. This mutant, named Pingu (Pgu), carries a missense mutation, an I402T substitution in the S6 segment of the voltage-gated potassium channel Kcna2. The gene Kcna2 encodes the voltage-gated potassium channel ␣-subunit Kv1.2, which is abundantly expressed in the large axon terminals of basket cells that make powerful axo-somatic synapses onto Purkinje cells. Patch clamp recordings from cerebellar slices revealed an increased frequency and amplitude of spontaneous GABAergic inhibitory postsynaptic currents and reduced action potential firing frequency in Purkinje cells, suggesting that an increase in GABA release from basket cells is involved in the motor incoordination in Pgu mice. In line with immunochemical analyses showing a significant reduction in the expression of Kv1 channels in the basket cell terminals of Pgu mice, expression of homomeric and heteromeric channels containing the Kv1.2(I402T) ␣-subunit in cultured CHO cells revealed subtle changes in biophysical properties but a dramatic decrease in the amount of functional Kv1 channels. Pharmacological treatment with acetazolamide or transgenic complementation with wildtype Kcna2 cDNA partially rescued the motor incoordination in Pgu mice. These results suggest that independent of known mutations in Kcna1 encoding Kv1.1, Kcna2 mutations may be important molecular correlates underlying human cerebellar ataxic disease.Voltage-gated potassium channels play a key role in neuronal excitability and plasticity and are critical in establishing resting membrane potential and firing thresholds, repolarizing action potentials, and limiting excitability (1). Channels are unevenly distributed throughout the brain as a whole and also within individual neurons (2-10). Therefore, the particular utility of any given channel depends not only on its specific channel properties and stoichiometry but also on its particular localization and density within a cell or cellular compartment. In the cerebellum, the genes Kcna1 and Kcna2 encode the voltagegated potassium channel subunits Kv1.1 and Kv1.2, respectively, which contribute to the low voltage-activated potassium current I Kv1 and are coexpressed in the presynaptic GABAergic pinceaus of spontaneously firing basket cell interneurons that provide a strong inhibitory input to Purkinje cells (5-9). The shunting effect of this inhibitory conductance has been shown through modeling to have a steep correlation with the prolongation of Purkinje cell interspike intervals in vitro (11-13).The cerebellum is involved in the regulation of the initiation and timing of movements and is important for maintaining balance and posture (14). At the core of the cerebellar computational circuitry, the spontaneously spiking Purkinje cells integrate cerebral cortical and sensory, excitatory and inhibitory inputs encoding relevant information in their action potential discharge and communicate the information to the deep cerebell...

Regulator of G Protein Signaling 6 (RGS6) Protein Ensures Coordination of Motor Movement by Modulating GABAB Receptor Signaling

“…Cerebellar dysfunction manifests phenotypically as impaired performance on the rotating rod (rotarod) (26), a classic test for motor coordination in rodent models, with occasional gait abnormalities (27)(28)(29)(30). Gross examination of the carriage of RGS6 Ϫ/Ϫ mice on the rotarod revealed both a lowered stance and hip position compared with their WT counterparts ( Fig.…”

Margatoxin is a non-selective inhibitor of human Kv1.3 K+ channels

“…Importance of Kv1.1 expression in the nervus vagus in cardiac function was shown in mice (Glasscock et al, 2010) and the channel is involved in the glucose-stimulated insulin release in b-cells (Ma et al, 2011). Kv1.2 is expressed in different neurons Fulton et al, 2011;Utsunomiya et al, 2008;Wang et al, 1994) and the malfunction of both Kv1.1 and Kv1.2 channels were shown to cause cerebellar ataxia (Browne et al, 1994;Xie et al, 2010). Consequently, the use of Kv1.3 inhibitors with poor selectivity may alter the physiological functions mentioned above.…”

Structure, Molecular Modeling, and Function of the Novel Potassium Channel Blocker Urotoxin Isolated from the Venom of the Australian Scorpion Urodacus yaschenkoi

“…As the hK v 1.1 channel is closely related to hK v 1.2 and hK v 1.3 (Wang et al, 1994;Xie et al, 2010;Robbins and Tempel, 2012), urotoxin was additionally tested in the latter two channels. Urotoxin, at 10 nM, fully blocked the whole cell hK v 1.2 current (Fig.…”