Disease relevance of Kcna1

• Despite overall enlargement, the mceph/mceph brain appears structurally normal, without oedema, hydrocephaly or leukodystrophy, and with only minor astrocytosis [1].
• In contrast, neuromyotonia sera bound more strongly to Kv1.2 subunits than to Kv1.1 or Kv1 [2].
• A cellular model for long QT syndrome. Trapping of heteromultimeric complexes consisting of truncated Kv1.1 potassium channel polypeptides and native Kv1.4 and Kv1.5 channels in the endoplasmic reticulum [3].
• Cardiac-specific expression of a truncated Kv1.1 polypeptide (Kv1DN) attenuates the slow inactivating outward K(+) current (I(K,slow)), increases action potential duration (APD) and Q-T intervals, and induces spontaneous ventricular arrhythmias [4].
• The dramatic effects of DTX-K suggest a possible connection between SAD and episodic ataxia type 1 (EA1), a Kv1.1 potassium channelopathy [5].

Psychiatry related information on Kcna1

• Motor skills tests show that Kv1.1 null mice display a compromised ability to maintain balance on a thin stationary rod [6].
• Two other potassium channel subunits, Kv1.1 and Kv1.4, were not affected by either acute or chronic electroconvulsive shock [7].
• The distribution and modulation of neural cell adhesion molecule polysialylation state (NCAM PSA) and the consequence of antisense inactivation of the Kv1.1 potassium channel was investigated following avoidance learning in mice [8].

High impact information on Kcna1

• Currents expressed in naive CD4(+) lymphocytes are consistent with Kv1.1, Kv1.2, Kv1.3, and Kv1 [9].
• The contactin mutation does not affect sodium channel clustering at the nodes of Ranvier but alters the location of the Shaker-type Kv1.1 and Kv1.2 potassium channels [10].
• Immunoblotting confirmed the presence of Kv1.1, 1.2, 1.3, 1.5, 1.6, and 2.1, but not Kv1.4, in PASMCs [11].
• We recently have reported that suppression of the slowly inactivating component of the outward current, Islow, in ventricular myocytes of transgenic mice (long QT mice) overexpressing the N-terminal fragment and S1 segment of Kv1.1 resulted in a significant prolongation of action potential duration and the QT interval [12].
• At the cellular level, we propose that Kv1.1 deletion enhances excitability of the basket cells by selectively enhancing the likelihood of action potential propagation past axonal branch points [6].

Chemical compound and disease context of Kcna1

• We examined the neural control of the respiratory system of littermate wild-type (control) and Kv1.1-null mice during low O2 (hypoxia) [13].
• Kv1.1 channels of dorsal root ganglion neurons are inhibited by n-butyl-p-aminobenzoate, a promising anesthetic for the treatment of chronic pain [14].

Biological context of Kcna1

• There were no significant differences in intrinsic membrane properties and action potential shape between Kcna1-null and wild-type mice, consistent with previous findings in hippocampal slice recordings [15].
• When extracellular potassium was elevated and excitatory synaptic transmission was blocked, antidromic activation or short pulses of intracellular depolarizing current evoked voltage-dependent bursts of action potentials in the majority of cells recorded in Kcna1 null slices, but only single spikes in control slices [16].
• Two neurological mutants deafwaddler (dfw) and opisthotonos (opt) and a cluster of three Shaker-like potassium (K) channel genes Kcna1, Kcna5, and Kcna6 were all independently mapped to distal mouse chromosome six (Chr 6) [17].
• Together these results suggest (1) heteromeric assembly of Shaker-like channels is cotranslational, and (2) N207 glycosylation of Kv1.1 occurs but is not required for subunit assembly, transport, or function [18].
• We show that mceph/mceph mice have disturbed brain electrophysiology and experience recurrent behavioural seizures, in agreement with the abnormal electrical brain activity found in Shaker mutants [1].

Anatomical context of Kcna1

• METHODS: Intracellular recordings were obtained from CA3 pyramidal cells in hippocampal slices prepared from Kcna1-null and control littermates [16].
• Evidence of altered inhibition in layer V pyramidal neurons from neocortex of Kcna1-null mice [15].
• The voltage-gated potassium (Kv) channel subunit Kv1.1, encoded by the Kcna1 gene, is expressed strongly in the ventral cochlear nucleus (VCN) and the medial nucleus of the trapezoid body (MNTB) of the auditory pathway [19].
• Localization of Kv1.1 and Kv1.2, two K channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain [20].
• Pharmacological characterization of five cloned voltage-gated K+ channels, types Kv1.1, 1.2, 1.3, 1.5, and 3.1, stably expressed in mammalian cell lines [21].

Associations of Kcna1 with chemical compounds

• Our results show that a voltage-gated sodium channel (Scn1b) and a voltage-gated potassium channel (Kcna1) are differentially expressed in AGS and PTZ-induced epilepsy models as well as in QYS-treated animals [22].
• Gal(beta1-3)GalNAc binding sites did not have an obligatory co-localization with voltage-gated sodium channels or the potassium ion channels Kv1.1 and Kv1.5 and are thus not likely carried by these ion channels [23].
• To gain insight into the pathogenesis of these neuropathies, we examined the distribution of GM1 ganglioside and Gal(beta1-3)GalNAc moieties in nerve fibres and their relationship to voltage-gated sodium and potassium (Kv1.1, 1.5) channels at the nodes of Ranvier in peripheral nerves from human, rat and dystrophic mice [23].
• We demonstrated that overexpression of a cRNA encoding a truncated potassium channel polypeptide that contains the NH2 terminus and the first transmembrane segment (Kv1.1N206Tag) abolished the expression of Kv1.1 and Kv1.5 outward currents in Xenopus oocytes (Babila, T., Moscucci, A., Wang, H., Weaver, F. E. & Koren, G. (1994) Neuron 12, 615-626) [3].
• Overexpression of a dominant-negative truncated Kv1.1 (Kv1DN) polypeptide in the mouse heart resulted in marked attenuation of a 4-aminopyridine (4-AP)-sensitive current, I(K,slow1) [24].

Regulatory relationships of Kcna1

• Thus, Kv1.5 encodes the 4-AP-sensitive component of I(K,slow) in the mouse ventricle and confers sensitivity to 4-AP-induced prolongation of APD and QTC: Compensatory upregulation of Kv2.1 may explain the phenotypic differences between SWAP mice and the previously described transgenic mice expressing a truncated dominant-negative Kv1.1 construct [25].
• When Kv1.1 was expressed as a heterotetrameric complex with Kv1.5, block by DTX-K dominated, indicating that one or more subunits of Kv1.1 rendered the heterotetrameric channel sensitive to DTX-K [26].

Other interactions of Kcna1

• Of particular interest is the stark contrast between high level expression of Kv1.1 and very low level expression of Kv3.1 in the octopus cell area of the cochlear nucleus and in the lateral superior olivary nucleus [27].
• The non-Shaker Kv2.1 channel did not assemble with Kv1.1 or Kv1 [18].
• This property of CA3 neurons, seen particularly when tissue conditions become abnormal (e.g., elevated extracellular potassium), helps to explain the high seizure susceptibility of Kcna1-null mice [16].
• However, in contrast to the commonly demonstrated epilepsy-induced neurodegeneration, we find that the mceph mutation leads to seizures with a concomitant increase in brain size, without overt neural atrophy [1].
• These data suggest that the IGF system has an important role in the excessive growth of the mceph/mceph brains [28].

Analytical, diagnostic and therapeutic context of Kcna1

• We used the whole cell version of the patch clamp technique to record from MNTB neurons in brainstem slices from Kcna1-null (-/-) mice and their wild-type (+/+) and heterozygous (+/-) littermates [29].
• 4. Mouse L-cells transfected with Kv1.1 cDNA yielded 1000-4000 functional surface channels, and immune purification from Kv1.1 cells with Kv1.1 antisera produced a 57-59 kDa doublet on SDS-PAGE but not in sham-transfected cells [18].
• Interactions between MCEPH and other Kv1 subunits were studied in cell culture, Xenopus oocytes and the brain [30].
• 5. Using both in situ hybridization and immunocytochemistry, we have identified several cell types and tissues that express Kv1.1 RNA and protein [31].
• RT PCR on mRNA from enzymatically dissociated, isolated bipolar cells showed that these neurons express the Shaker-like K+ channels Kv1.1, Kv1.2, and Kv1 [32].

References