The Inherited Episodic Ataxias: How Well Do We Understand the Disease Mechanisms?
01 Feb 2001-The Neuroscientist (Sage PublicationsSage CA: Thousand Oaks, CA)-Vol. 7, Iss: 1, pp 80-88
TL;DR: This review evaluates the success of electrophysiological methods in explaining the mechanisms of two forms of episodic ataxia that are known to be caused by mutations of ion channels.
Abstract: The past few years have seen the elucidation of several neurological diseases caused by inherited mutations of ion channels In contrast to many other types of genetic disorders, the "channelopathies" can be studied with high precision by applying electrophysiological methods This review evaluates the success of this approach in explaining the mechanisms of two forms of episodic ataxia that are known to be caused by mutations of ion channels: episodic ataxia type 1 (EA1, caused by K+ channel mutations) and episodic ataxia type 2 (EA2, caused by Ca2+ channel mutations) Although both of these disorders are rare, they raise many important questions about the roles of identified channels in brain function Indeed, a resolution of the mechanisms by which both diseases occur will represent a major milestone in understanding diseases of the CNS, in addition to opening the way to novel possible treatments
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TL;DR: The hypothesis that a pronounced loss of P/Q-type Ca2+ channel function underlies the pathophysiology of EA-2 and PA is supported and AY1593/1594D and G293R form at least partially functional channels.
103 citations
TL;DR: This review examines the current understanding of episodic ataxia type 1, focusing on its clinical and genetic features, pathophysiology, and treatment.
87 citations
TL;DR: It is reported that Na(v)1.8 can be functionally expressed at physiological levels within Purkinje cells, and that its expression alters the activity of these neurons in three ways: first, by increasing the amplitude and duration of action potentials; second, by decreasing the proportion ofaction potentials that are conglomerate; and third, by contributing to the production of sustained, pacemaker-like impulse trains in response to depolarization.
59 citations
TL;DR: The results demonstrate that the human Kvβ1.1 and Kv β1.2 subunits modulated the functional properties of tandemly linked Kv1.4.4‐1.x subunits, and alter the fast inactivation and repriming properties of the channels by decreasing both the rate and degree of N‐type in activation and by accelerating the recovery from fast in activation.
Abstract: Episodic ataxia type 1 (EA1) is an autosomal dominant neurological disorder characterized by constant muscle rippling movements (myokymia) and episodic attacks of ataxia. Several heterozygous point mutations have been found in the coding sequence of the voltage-gated potassium channel gene KCNA1 (hKv1.1), which alter the delayed-rectifier function of the channel. Shaker-like channels of different cell types may be formed by unique hetero-oligomeric complexes comprising Kv1.1, Kv1.4 and Kvbeta1.x subunits. Here we show that the human Kvbeta1.1 and Kvbeta1.2 subunits modulated the functional properties of tandemly linked Kv1.4-1.1 wild-type channels expressed in Xenopus laevis oocytes by (i) increasing the rate and amount of N-type inactivation, (ii) slowing the recovery rate from inactivation, (iii) accelerating the cumulative inactivation of the channel and (iv) negatively shifting the voltage dependence of inactivation. To date, the role of the human Kv1.4-1.1, Kv1.4-1.1/Kvbeta1.1 and Kv1.4-1.1/Kvbeta1.2 channels in the aetiopathogenesis of EA1 has not been investigated. Here we also show that the EA1 mutations E325D, V404I and V408A, which line the ion-conducting pore, and I177N, which resides within the S1 segment, alter the fast inactivation and repriming properties of the channels by decreasing both the rate and degree of N-type inactivation and by accelerating the recovery from fast inactivation. Furthermore, the E325D, V404I and I177N mutations shifted the voltage dependence of the steady-state inactivation to more positive potentials. The results demonstrate that the human Kvbeta1.1 and Kvbeta1.2 subunits regulate the proportion of wild-type Kv1.4-1.1 channels that are available to open. Furthermore, EA1 mutations alter heteromeric channel availability which probably modifies the integration properties and firing patterns of neurones controlling cognitive processes and body movements.
51 citations
Cites background from "The Inherited Episodic Ataxias: How..."
...Although several lines of evidence indicate that defective delayed rectifier channels and cerebellar dysfunction account for some of the symptoms displayed by affected individuals, the molecular and neurological mechanisms of EA1 are not completely understood (Kullmann et al., 2001)....
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TL;DR: This review provides an overview of recent patents on emerging K(+) channel blockers and activators (openers) with potential for development as new and improved nervous system therapeutic agents.
Abstract: Potassium (K+) channels are the most heterogeneous and widely distributed class of ion channels. K(+) channels are dynamic pore-forming transmembrane proteins known to play important roles in all cell types underlying both normal and pathophysiological functions. Essential for such diverse physiological processes as nerve impulse propagation, muscle contraction, cellular activation and the secretion of biologically active molecules, various K(+) channels are recognized as potential therapeutic targets in the treatment of multiple sclerosis, Alzheimer's disease, Parkinson's disease, epilepsy, stroke, brain tumors, brain/spinal cord ischemia, pain and schizophrenia, migraine, as well as cardiac arrhythmias, pulmonary hypertension, diabetes, cervical cancer, urological diseases and sepsis. In addition to their importance as therapeutic targets, certain K(+) channels are gaining attention for their beneficial roles in anesthesia, neuroprotection and cardioprotection. The K(+) channel gene families (subdividing into multiple subfamilies) include voltage-gated (K(v): K(v)1-K(v)12 or KCNA-KCND, KCNF-KCNH, KCNQ, KCNS), calcium-activated (K(Ca): K(Ca)1-K(Ca)5 or KCNM-KCNN), inwardly rectifying (K(ir): K(ir)1-K(ir)7 or KCNJ) and background/leak or tandem 2-pore (K(2P): K(2P)1-K(2P)7, K(2P)9-K(2P)10, K(2P)12-K(2P)13, K(2P)15-K(2P)18 or KCNK) K(+) channels. Worldwide, the pharmaceutical industry is actively developing better strategies for targeting ion channels, in general, and K(+) channels, in particular, already generating over $6 billion in sales per annum from drugs designed to block or modulate ion channel function. This review provides an overview of recent patents on emerging K(+) channel blockers and activators (openers) with potential for development as new and improved nervous system therapeutic agents.
45 citations
References
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TL;DR: A brain-specific P/Q-type Ca2+ channel alpha1-subunit gene, CACNL1A4, covering 300 kb with 47 exons is characterized, revealing polymorphic variations, including a (CA)n-repeat (D19S1150), a (CAG) n-repeat in the 3'-UTR, and different types of deleterious mutations in FHM and EA-2.
2,264 citations
TL;DR: It is concluded that a small polyglutamine expansion in the human α1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.
Abstract: A polymorphic CAG repeat was identified in the human α1A voltage-dependent calcium channel subunit. To test the hypothesis that expansion of this CAG repeat could be the cause of an inherited progressive ataxia, we genotyped a large number of unrelated controls and ataxia patients. Eight unrelated patients with late onset ataxia had alleles with larger repeat numbers (21‐27) compared to the number of repeats (4‐16) in 475 non‐ataxia individuals. Analysis of the repeat length in families of the affected individuals revealed that the expansion segregated with the phenotype in every patient. We identified six isoforms of the human α1A calcium channel subunit. The CAG repeat is within the open reading frame and is predicted to encode glutamine in three of the isoforms. We conclude that a small polyglutamine expansion in the human α1A calcium channel is most likely the cause of a newly classified autosomal dominant spinocerebellar ataxia, SCA6.
1,558 citations
TL;DR: Mutation analysis of the KCNA1 coding region in families identified four different missense point mutations present in the heterozygous state, indicating that EA/myokymia can result from mutations in this gene.
Abstract: Episodic ataxia (EA) is a rare, familial disorder producing attacks of generalized ataxia, with normal or near-normal neurological function between attacks. One type of EA is characterized by brief episodes of ataxia with myokymia (rippling of muscles) evident between attacks. Linkage studies in four such families suggested localization of an EA/myokymia gene near the voltage gated K+ channel gene, KCNA1 (Kv1.1), on chromosome 12p. Mutation analysis of the KCNA1 coding region in these families identified four different missense point mutations present in the heterozygous state, indicating that EA/myokymia can result from mutations in this gene.
728 citations
TL;DR: The co-localization of two Shaker-like voltage-gated K+-channel proteins is described, indicating that the two polypeptides occur in subcellular regions where rapid membrane repolarization may be important and that they form heteromultimeric channels in vivo.
Abstract: Voltage-gated potassium (K+) channels display a wide variety of conductances and gating properties in vivo This diversity can be attributed not only to the presence of many K(+)-channel gene products, but also to the possibility that different K(+)-channel subunits co-assemble to form heteromultimeric channels in vivo When expressed in Xenopus oocytes or transfected cells, K(+)-channel polypeptides assemble to form tetramers Certain combinations of Shaker-like subunits have been shown to co-assemble, forming heteromultimeric channels with distinct properties It is not known, however, whether K(+)-channel polypeptides form heteromultimeric channels in vivo Here we describe the co-localization of two Shaker-like voltage-gated K(+)-channel proteins, mKv11 and mKv12, in the juxtaparanodal regions of nodes of Ranvier in myelinated axons, and in terminal fields of basket cells in mouse cerebellum We also show that mKv11 and mKv12 can be coimmunoprecipitated with specific antibodies that recognize only one of them These data indicate that the two polypeptides occur in subcellular regions where rapid membrane repolarization may be important and that they form heteromultimeric channels in vivo
616 citations
TL;DR: A site-directed anti-peptide antibody (anti-CNA1) directed against the alpha 1 subunit of class A calcium channels (alpha 1A) recognized a protein of approximately 190-200 kDa in immunoblot and immunoprecipitation analyses of rat brain glycoproteins, defining a unique pattern of localization of class C calcium channels in the cell bodies, dendrites, and presynaptic terminals of most central neurons.
Abstract: A site-directed anti-peptide antibody (anti-CNA1) directed against the alpha 1 subunit of class A calcium channels (alpha 1A) recognized a protein of approximately 190-200 kDa in immunoblot and immunoprecipitation analyses of rat brain glycoproteins. Calcium channels recognized by anti-CNA1 were distributed throughout the brain with a high concentration in the cerebellum. Calcium channels having alpha 1A subunits were concentrated in presynaptic terminals making synapses on cell bodies and on dendritic shafts and spines of many classes of neurons and were especially prominent in the synapses of the parallel fibers of cerebellar granule cells on Purkinje neurons where their localization in presynaptic terminals was confirmed by double labeling with the synaptic membrane protein syntaxin or the microinjected postsynaptic marker Neurobiotin. They were present in lower density in the surface membrane of dendrites of most major classes of neurons. There was substantial labeling of Purkinje cell bodies, but less intense staining of the cell bodies of hippocampal pyramidal neurons, layer V pyramidal neurons in the dorsal cortex, and most other classes of neurons in the forebrain and cerebellum. Scattered cell bodies elsewhere in the brain were labeled at low levels. These results define a unique pattern of localization of class A calcium channels in the cell bodies, dendrites, and presynaptic terminals of most central neurons. Compared to class B N-type calcium channels, class A calcium channels are concentrated in a larger number of presynaptic nerve terminals implying a more prominent role in neurotransmitter release at many central synapses.
583 citations