Episodic ataxia type 1 mutation F184C alters Zn<sup>2+</sup>-induced modulation of the human K<sup>+</sup> channel Kv1.4-Kv1.1/Kvβ1.1

Imbrici, Paola; D’Adamo, Maria Cristina; Cusimano, Antonella; Pessia, Mauro

doi:10.1152/ajpcell.00259.2006

Cited by 29 publications

(17 citation statements)

References 70 publications

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“…Zn 2+ is released from mossy fiber terminals in the hippocampus, and from the basket cell terminals of the cerebellum (Assaf and Chung, 1984) where Kv1 channel activity likely is subjected to Zn 2+ modulation. Indeed, homomeric and heteromeric channels containing Kv1 subunits are inhibited by extracellular Zn 2+ , and a distinct EA1 mutation increases several folds the Zn 2+ sensitivity of these channels (Cusimano et al, 2004; Imbrici et al, 2007). Whether Zn 2+ plays a role in triggering epilepsy-like symptoms in EA1 remains an intriguing hypothesis.…”

Section: Kv11 Channelepsymentioning

confidence: 99%

K+ channelepsy: progress in the neurobiology of potassium channels and epilepsy

D’Adamo

Catacuzzeno

Giovanni

et al. 2013

Front. Cell. Neurosci.

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105

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K+ channels are important determinants of seizure susceptibility. These membrane proteins, encoded by more than 70 genes, make the largest group of ion channels that fine-tune the electrical activity of neuronal and non-neuronal cells in the brain. Their ubiquity and extremely high genetic and functional diversity, unmatched by any other ion channel type, place K+ channels as primary targets of genetic variations or perturbations in K+-dependent homeostasis, even in the absence of a primary channel defect. It is therefore not surprising that numerous inherited or acquired K+ channels dysfunctions have been associated with several neurologic syndromes, including epilepsy, which often generate confusion in the classification of the associated diseases. Therefore, we propose to name the K+ channels defects underlying distinct epilepsies as “K+ channelepsies,” and introduce a new nomenclature (e.g., Kx.y-channelepsy), following the widely used K+ channel classification, which could be also adopted to easily identify other channelopathies involving Na+ (e.g., Navx.y-phenotype), Ca2+ (e.g., Cavx.y-phenotype), and Cl− channels. Furthermore, we discuss novel genetic defects in K+ channels and associated proteins that underlie distinct epileptic phenotypes in humans, and analyze critically the recent progress in the neurobiology of this disease that has also been provided by investigations on valuable animal models of epilepsy. The abundant and varied lines of evidence discussed here strongly foster assessments for variations in genes encoding for K+ channels and associated proteins in patients with idiopathic epilepsy, provide new avenues for future investigations, and highlight these proteins as critical pharmacological targets.

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Section: Kv11 Channelepsymentioning

confidence: 99%

K+ channelepsy: progress in the neurobiology of potassium channels and epilepsy

D’Adamo

Catacuzzeno

Giovanni

et al. 2013

Front. Cell. Neurosci.

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105

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“…These models employ several novel concepts and approaches and provide a framework for the study not only of IP3R1-associated ataxias , but of various SCAs involving mutations of other molecules in the model, such as potassium channels [65,79,101,102] and calcium channels [29,76,77,103]. …”

Section: Discussionmentioning

confidence: 99%

Computational analysis of calcium signaling and membrane electrophysiology in cerebellar Purkinje neurons associated with ataxia

Brown

Loew

2012

BMC Systems Biology

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BackgroundMutations in the smooth endoplasmic reticulum (sER) calcium channel Inositol Trisphosphate Receptor type 1 (IP3R1) in humans with the motor function coordination disorders Spinocerebellar Ataxia Types 15 and 16 (SCA15/16) and in a corresponding mouse model, the IP3R1delta18/delta18 mice, lead to reduced IP3R1 levels. We posit that increasing IP3R1 sensitivity to IP3 in ataxias with reduced IP3R1 could restore normal calcium response. On the other hand, in mouse models of the human polyglutamine (polyQ) ataxias, SCA2, and SCA3, the primary finding appears to be hyperactive IP3R1-mediated calcium release. It has been suggested that the polyQ SCA1 mice may also show hyperactive IP3R1. Yet, SCA1 mice show downregulated gene expression of IP3R1, Homer, metabotropic glutamate receptor (mGluR), smooth endoplasmic reticulum Ca-ATP-ase (SERCA), calbindin, parvalbumin, and other calcium signaling proteins.ResultsWe create a computational model of pathological alterations in calcium signaling in cerebellar Purkinje neurons to investigate several forms of spinocerebellar ataxia associated with changes in the abundance, sensitivity, or activity of the calcium channel IP3R1. We find that increasing IP3R1 sensitivity to IP3 in computational models of SCA15/16 can restore normal calcium response if IP3R1 abundance is not too low. The studied range in IP3R1 levels reflects variability found in human and mouse ataxic models. Further, the required fold increases in sensitivity are within experimental ranges from experiments that use IP3R1 phosphorylation status to adjust its sensitivity to IP3. Results from our simulations of polyglutamine SCAs suggest that downregulation of some calcium signaling proteins may be partially compensatory. However, the downregulation of calcium buffer proteins observed in the SCA1 mice may contribute to pathology. Finally, our model suggests that the calcium-activated voltage-gated potassium channels may provide an important link between calcium metabolism and membrane potential in Purkinje cell function.ConclusionThus, we have established an initial platform for computational evaluation and prediction of ataxia pathophysiology. Specifically, the model has been used to investigate SCA15/16, SCA1, SCA2, and SCA3. Results suggest that experimental studies treating mouse models of any of these ataxias with appropriately chosen peptides resembling the C-terminal of IP3R1 could adjust receptor sensitivity, and thereby modulate calcium release and normalize IP3 response. In addition, the model supports the hypothesis of IP3R1 supersensitivity in SCA1.

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“…These channels, located in the axons of neurons, do not affect the first action potential but increase the action potential threshold and guarantee the correct propagation of electrical signals ( Jan and Jan, 2012). Kv1.1 co-assembles with Kv1.4 at the hippocampal mossy fiber boutons, where they mediate neuronal activity-dependent processes involved in synaptic plasticity ( Imbrici et al, 2007). The KCNQ2–5 channels are expressed in different combinations in neurons.…”

Section: General Features Of Ion Channelsmentioning

confidence: 99%

Major channels involved in neuropsychiatric disorders and therapeutic perspectives

Imbrici¹,

Camerino²,

Tricarico³

2013

Front. Genet.

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121

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Voltage-gated ion channels are important mediators of physiological functions in the central nervous system. The cyclic activation of these channels influences neurotransmitter release, neuron excitability, gene transcription, and plasticity, providing distinct brain areas with unique physiological and pharmacological response. A growing body of data has implicated ion channels in the susceptibility or pathogenesis of psychiatric diseases. Indeed, population studies support the association of polymorphisms in calcium and potassium channels with the genetic risk for bipolar disorders (BPDs) or schizophrenia. Moreover, point mutations in calcium, sodium, and potassium channel genes have been identified in some childhood developmental disorders. Finally, antibodies against potassium channel complexes occur in a series of autoimmune psychiatric diseases. Here we report recent studies assessing the role of calcium, sodium, and potassium channels in BPD, schizophrenia, and autism spectrum disorders, and briefly summarize promising pharmacological strategies targeted on ion channels for the therapy of mental illness and related genetic tests.

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Episodic ataxia type 1 mutation F184C alters Zn²⁺-induced modulation of the human K⁺ channel Kv1.4-Kv1.1/Kvβ1.1

Abstract: Imbrici P, D'Adamo MC, Cusimano A, Pessia M. Episodic ataxia type 1 mutation F184C alters Zn 2ϩ -induced modulation of the human K

Cited by 29 publications

References 70 publications

K+ channelepsy: progress in the neurobiology of potassium channels and epilepsy

K+ channelepsy: progress in the neurobiology of potassium channels and epilepsy

Computational analysis of calcium signaling and membrane electrophysiology in cerebellar Purkinje neurons associated with ataxia

Major channels involved in neuropsychiatric disorders and therapeutic perspectives

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Episodic ataxia type 1 mutation F184C alters Zn2+-induced modulation of the human K+ channel Kv1.4-Kv1.1/Kvβ1.1

Abstract: Imbrici P, D'Adamo MC, Cusimano A, Pessia M. Episodic ataxia type 1 mutation F184C alters Zn 2ϩ -induced modulation of the human K

Cited by 29 publications

References 70 publications

K+ channelepsy: progress in the neurobiology of potassium channels and epilepsy

K+ channelepsy: progress in the neurobiology of potassium channels and epilepsy

Computational analysis of calcium signaling and membrane electrophysiology in cerebellar Purkinje neurons associated with ataxia

Major channels involved in neuropsychiatric disorders and therapeutic perspectives

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Product

Resources

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Episodic ataxia type 1 mutation F184C alters Zn²⁺-induced modulation of the human K⁺ channel Kv1.4-Kv1.1/Kvβ1.1