Neuronal voltage-gated potassium channel complex autoimmunity in children

Autoimmunity targeting voltage-gated potassium channel complexes have not been systematically documented in children. Identified in the Neuroimmunology Laboratory records of Mayo Clinic were 12 seropositive children, 7 among 252 Mayo Clinic pediatric patients tested on a service basis for serologic evidence of neurologic autoimmunity (June 2008-April 2010), 4 during the assay's preimplementation validation (before June 2008) and 1 non-Mayo patient with available clinical information. Neurologic manifestations were subacute and multifocal. Three had global developmental regression, 6 movement disorders, 4 dysarthria, 3 seizures, 1 Satoyoshi syndrome, 1 painful red feet, 2 insomnia, 2 gastrointestinal dysmotility, and 2 small fiber neuropathy. Neoplasia was found in 1 child. Treating physicians recorded improvement in all 7 children who received immunotherapy. Neurologic symptom relapse occurred in 3 of 6 children after ceasing immunotherapy. These findings highlight a diverse clinical spectrum of neuronal potassium channel complex autoimmunity in children, and they illustrate benefit from early initiated immunotherapy, with a tendency to relapse when therapy ceases. Diagnosis is generally delayed in the process of eliminating neurodegenerative causes. Currently 2.7% of pediatric sera evaluated for neurologic autoimmunity are positive for neuronal potassium channel complex-reactive immunoglobulin G. The frequency and full spectrum of neurologic accompaniments remains to be determined.     

The Kv7 potassium channel activator flupirtine affects clinical excitability parameters of myelinated axons in isolated rat sural nerve

Flupirtine is an activator of Kv7 (KCNQ/M) potassium channels that has found clinical use as an analgesic with muscle relaxant properties. Kv7 potassium channels are expressed in axonal membranes and pharmacological activation of these channels may restore abnormal nerve excitability. We have examined the effect of flupirtine on the electrical excitability of myelinated axons in isolated segments of rat sural nerve. Axonal excitability was studied in vitro with the same parameters used by clinical neurophysiologists to assess peripheral nerve excitability in situ . Application of flupirtine in low micromolar concentrations resulted in an increase in threshold current, a reduction of refractoriness and an increase in post-spike superexcitability. These effects are consistent with an increase in Kv7 conductance and membrane hyperpolarization. Flupirtine also enhanced and prolonged the late, long-lasting period of axonal subexcitability that follows a short burst of action potentials. This effect was blocked by XE 991 (10 µM), an antagonist of Kv7 channels. In summary, flupirtine affects measures of excitability that are altered in the myelinated axons of patients with peripheral nerve disorders. This indicates that neuropathies with abnormal nerve excitability parameters corresponding to those affected by flupirtine may benefit from activation of axonal Kv7 potassium channels.     

Neuronal trafficking of voltage-gated potassium channels

The computational ability of CNS neurons depends critically on the specific localization of ion channels in the somatodendritic and axonal membranes. Neuronal dendrites receive synaptic inputs at numerous spines and integrate them in time and space. The integration of synaptic potentials is regulated by voltage-gated potassium (Kv) channels, such as Kv4.2, which are specifically localized in the dendritic membrane. The synaptic potentials eventually depolarize the membrane of the axon initial segment, thereby activating voltage-gated sodium channels to generate action potentials. Specific Kv channels localized in the axon initial segment, such as Kv1 and Kv7 channels, determine the shape and the rate of action potentials. Kv1 and Kv7 channels present at or near nodes of Ranvier and in presynaptic terminals also influence the propagation of action potentials and neurotransmitter release. The physiological significance of proper Kv channel localization is emphasized by the fact that defects in the trafficking of Kv channels are observed in several neurological disorders including epilepsy. In this review, we will summarize the current understanding of the mechanisms of Kv channel trafficking and discuss how they contribute to the establishment and maintenance of the specific localization of Kv channels in neurons.     

A possible link of oxaliplatin-induced neuropathy with potassium channel deficit

Introduction: The neurotoxic side effects of oxaliplatin (a reference drug in the treatment of digestive tract tumors) can force suspension of treatment. The mechanisms of neuropathy are unclear. We aimed to simulate oxaliplatin‐induced hyperactivity in myelinated axons (MA) based on published experimental data. Methods: A Hodgkin–Huxley‐type multi‐cable MA model was used, which took into account active internodal processes and accumulation of ions in MA with 21 nodes. Results: Even a very short (110–220 μm) internodal region devoid of potassium channels was sufficient to produce after‐discharges in response to a saltatory action potential. An increase in the density of sodium channels, slowdown of their inactivation, and negative shifts along one node–internode region of the voltage dependence of sodium and potassium activation and of sodium inactivation induced no after‐discharge. Conclusion: A combination of sodium channel blockers with drugs that obstruct the blockage of potassium channels or contribute to their opening could be effective in preventing oxaliplatin‐induced “hyperexcitability.” Muscle Nerve, 2012     

A recalcitrant case of encephalitis with voltage-gated potassium channel antibodies

We report the case of a 65-year-old man who had encephalitis with a high titer of voltage-gated potassium channel antibodies (VGKC-Abs). His initial symptoms included memory disturbance, confusion, and seizures. Laboratory tests revealed a low plasma sodium concentration and a strong positive result for VGKC-Abs. A diffusion-weighted magnetic resonance imaging (MRI) scan showed a high intensity lesion within the right basal ganglia, which later showed normal intensity. The patient's initial symptoms resolved without any treatment. During the first relapse, the patient experienced consciousness disturbance and an increased number of seizures than that observed initially. A diffusion weighted MRI scan showed a high intensity lesion within the right hippocampus, and a fluid attenuated inversion recovery (FLAIR) weighted MRI scan showed high intensity lesions within the right hippocampus, right thalamus, and pons. The patient's symptoms and the MRI abnormalities resolved with prednisolone therapy. During the second relapse, he again experienced consciousness disturbance and an increased number of seizures than that observed initially. Diffusion-and FLAIR weighted MRI scans showed high intensity lesions within the right thalamus. However, the array of immunosuppressive treatments used during the first relapse was not as effective during the second relapse. The serum VGKC-Ab titers before steroid therapy during the first relapse and after immunosuppressive treatment during the second relapse were 1,252 pmol/L and 22.4 pmol/L, respectively. Brain MRI revealed signal changes in the basal ganglia at the onset of disease, in the limbic area during the first relapse, and in the thalamus during the second relapse. VGKC-Ab-associated encephalopathy is usually considered a benign autoimmune disorder; however, in our case, the encephalitis gradually became intractable to various immunosuppressive treatments, and unique MRI abnormalities were observed.     

Neuronal differentiation of Ca channel by nerve growth factor

The inhibitory effect of nicardipine, a potent Ca²⁺ channel blocker in muscular cells, on the Ca²⁺ channel of clonal rat pheochromocytoma cells (PC12h) and cultured rat adrenal medullary cells was studied during the neuronal differentiation mediated by nerve growth factor (NGF). Nicardipine at nM-order concentrations suppressed the high-K⁺-evoked, Ca²-dependent release of preloaded [³H]norepinephrine from PC12h cells and adrenal medullary cells, whereas it scarcely inhibited the release from the cultured rat brainstem cells. The inhibitory actions of nicardipine on both PC12h and newborn rat adrenal medullary cells were significantly decreased after these cells were cultured in the presence of NGF. These results suggest that the changes in Ca²⁺ channel are accompanied by the neuronal differentiation mediated by NGF.     

Benign familial neonatal epilepsy with mutations in two potassium channel genes

The significant progress made over the past year in understanding the basis for a form of neonatal seizures can be attributed to the successful positional cloning of two new voltage-gated potassium channel genes. Expression studies have increased our understanding of the biology of these channels and their role in epilepsy.     

It's "juxta" potassium channel!

Neuronal excitability depends on the appropriate expression and localization of ion channels. Juxtaparanodal Kv1 channels have been used as a model to study the role of neuroglial interactions in regulating the expression and localization of channels in myelinated axons. Recent advances in our understanding of the composition of juxtaparanodal Kv1 channel protein complexes as well as the cellular and molecular mechanisms underlying their localization at juxtaparanodes are discussed.     

Voltage-gated potassium channel antibodies in limbic encephalitis

We found voltage-gated potassium channel (VGKC) antibodies in 4 of 15 patients with limbic encephalitis (LE). Two patients with idiopathic LE had high VGKC antibody levels (>800 pM; controls <100 pM), that fell in parallel with a clinical response to immunotherapy. Two patients with lower VGKC antibodies (170 pM, 300 pM) had lung cancer (radiological evidence only in one) and the LE improved with immunotherapy in one. The other 11 patients without VGKC antibodies had paraneoplastic LE and eight onconeural antibodies (Hu in 6; Ma2 in 2). VGKC antibodies do not unambiguously discriminate between idiopathic or paraneoplastic LE but probably indicate a good response to immunotherapy.     

The timing of channel opening during miniature end-plate currents

Many chemical transmitters act by opening channels with exponentially distributed life-times. We present a way to analyze a synaptic current in terms of its component channels. We can estimate the numbers and times of channel opening within the synaptic current. This approach is used to study miniature end-plate currents (m.e.p.c.s) at the frog neuromuscular junction. The results support the idea that some transmitter rebinds after dissociation from post-synaptic receptors, and suggest that the time of channel closing is related to the time at which acetylcholine leaves the receptor.     

The voltage-gated potassium channel KCNQ2 in Taiwanese children with febrile convulsions

Mutations in the voltage-gated potassium channel genes KCNQ2 and KCNQ3 have been found to cause benign familial neonatal convulsions. Recent studies provided evidence that KCNQ2 and KCNQ3 contribute to the M-current, which regulates the subthreshold electrical excitability in the CNS. Febrile convulsions represent the majority of childhood seizures, and show a strong family history, suggesting a genetic predisposition. By performing an association study, we investigated whether KCNQ2 gene polymorphisms can be used as markers of susceptibility to febrile convulsions. These data suggest that the KCNQ2 gene might not be a useful marker for prediction of the susceptibility of febrile convulsions.     

Lymphocyte-specific inducible expression of potassium channel beta subunits

Many studies have shown that voltage-gated potassium (Kv) channel activity is essential for T-lymphocyte proliferation. The IL-2-inducible neuroimmune gene, I2rf5 is the mouse homologue of the rat Kvβ2 subunit. In this study we show that in addition to constitutive expression in adult murine brain, expression of Kv channel subunits β1.1 and β2.1 is inducible in a cloned T-helper cell line stimulated with IL-2 and in normal murine splenocytes stimulated with Con A or LPS. This expression pattern appears to be lymphocyte specific, because stimulated fibroblasts and vascular smooth muscle cells do not express Kvβ channel subunit mRNA. These observations suggest that Kvβ subunit expression is tissue specific and inducible in stimulated lymphocytes. Because Kvβ subunits modulate K⁺ channel activity, the inducible and variable expression of these subunits in lymphocytes may represent an additional regulatory mechanism for lymphocyte proliferation.