Kv1.1 Channelopathies: Pathophysiological Mechanisms and Therapeutic Approaches
Abstract
:1. Kv1.1 Channel Expression and Physiological Roles
2. Diseases Associated with Kv1.1 Channel Dysfunction
2.1. Clinical Aspects and Therapeutic Management of Episodic Ataxia Type 1
2.2. Functional Consequences of Episodic Ataxia Type 1 Mutations and Genotype-Phenotype Correlation
2.3. Kv1.1 Channel Involvement in Epilepsy
3. Kv1.1-Targeted Pharmacological Approaches
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Mutation | Position | Clinical Symptoms | Functional Defects | Treatment | References |
---|---|---|---|---|---|
R86Q | N-term | Severe stiffness, muscle cramps, pain | NA | Clonazepam ineffective | [84] |
R167M | S1 | Ataxia, dysarthria, neuromyotonia | Non-functional channels and dominant-negative effect | NA | [85] |
A170S | S1 | Cerebellar ataxia | NA | NA | [86] |
V174F | S1 | Ataxia, myokymia, paroxsymal choreoathetosis | Non-functional channels | ACTZ and CBZ ineffective, phenytoin effective | [49,76,87] |
I177N | S1 | Ataxia, myokymia | Reduced current density and dominant-negative effect, positive shift of voltage-dependent activation, slower activation, faster deactivation | NA | [75] |
F184C | S1 | Severe ataxia, myokymia, tremors, weakness, stiffness, visual disturbances, epilepsy | Reduced current density and positive shift of voltage-dependent activation | Phenytoin partially effective | [47,49,52,76,87] |
C185W | S1 | Ataxia, myokymia, stiffness, migraine, hyperthermia, short-sleep duration | Non-functional channels and dominant-negative effect | NA | [54,62,85] |
T226A/M | S2 | Ataxia, myokymia | Reduced surface expression, positive shift of voltage dependence of activation, slower deactivation, slower activation | NA | [88] |
T226K | S2 | Myokymia, leg hypertrophy, stiffness | Non-functional channels and dominant-negative effect | CBZ effective | [89] |
T226R | S2 | Ataxia, myokymia, and epilepsy | Reduced current density | CBZ and ACTZ effective; phenobarbital, phenytoin, and valproate ineffective | [57,66] |
T226R | S2 | Hypercontracted posture, skeletal deformities, stiffness | NA | NA | [58] |
T226R | S2 | Cataplexy without ataxia, sleep disturbances | NA | ACTZ discontinued | [61] |
R239S | S2 | Ataxia, myokymia | Non-functional channels | NA | [49,76,87] |
A242P | S2 | Ataxia, myokymia, epilepsy | Reduced current density | ACTZ ineffective, lamotrigine effective | [57,85] |
P244H | S2–S3 | Neuromyotonia without ataxia | Similar to WT | NA | [57] |
F249C | S2–S3 | Ataxia, malignant hyperthermia | Nonfunctional channels | NA | [63] |
F249I | S2–S3 | Ataxia and myokymia | Nonfunctional | NA | [49,76,87] |
F250stop | S2–S3 | Ataxia, myokymia, paroxysmal shortness of breath | NA | NA | [65] |
N255D | S3 | Hypomagnesemia | Reduced current density and dominant-negative effect | NA | [41] |
N255K | S3 | Paroxysmal kinesigenic dyskinesia | Reduced current density, dominant-negative effect, positive shift of voltage-dependent activation | NA | [68] |
I262M de novo | S3 | Ataxia, myokymia, stiffness, tremor, lower limb spasticity | Reduced current density and dominant-negative effect | Sodium valproate, diaminopyridine and phenytoin ineffective; ACTZ and CBZ worsened tremor; gabapentin and clonazepam effective for muscle stiffness | [69] |
I262T | S3 | Ataxia, distal weakness, paresis of foot extensors, stiffness | Reduced current density and dominant-negative effect | NA | [59,60] |
E283K | S3–S4 | Ataxia, myokymia, metabolic alterations, altered mechanosensation | Reduced current density, positive shift of voltage-dependent activation, slower activation | CBZ effective | [64] |
V299I | S4 | Generalized myokymia and paramyotonya (due to SCN4A mutation) | Reduced current density and dominant-negative effect, positive shift of voltage-dependent activation | NA | [90] |
F303V | S4 | Ataxia, myokymia, dizziness, slurred speech | Reduced current density, positive shift of voltage-dependent activation, slower activation, faster deactivation, increased C-type inactivation | NA | [78] |
L305F | S4 | Remittent ataxia, neuromyotonya, cramps, stiffness, hypertrophy | NA | Clonazepam, CBZ, and amitriptyline ineffective | [91] |
R307C | S4 | Ataxia, myokymia, headache, visual disturbance, nausea, weakness, slurred speech | Non-functional channels and dominant-negative effect | NA | [55] |
G311D de novo | S4–S5 | Remittent ataxia, myokymia, diplopia | Reduced current density | ACTZ, oxcarbazepine, and valproate discontinued | [67] |
G311S | S4–S5 | Ataxia | Reduced current density, positive shift of voltage-dependent activation | NA | [88] |
I314T | S4–S5 | Cataplexy without ataxia, sleep disturbances | NA | ACTZ discontinued | [61] |
L319R | S4–S5 | Paroxysmal kinesigenic dyskinesia without ataxia, dysarthria, seizure | Reduced current density and dominant-negative effect, positive shift of voltage-dependent activation | CBZ and oxcarbazepine effective | [68] |
R324T | S4–S5 | Ataxia, epilepsy, and signs of paroxysmal kinesigenic dyskinesia | Reduced current density | ACTZ ineffective, CBZ effective | [74] |
E325D | S4–S5 | Ataxia, myokymia | Reduced current, positive shift of voltage-dependent activation | ACTZ discontinued | [50,76,77,87] |
L328V | S5 | Hypomagnesemia, muscle cramps, tetany | Reduced current and dominant-negative effect | Mg2+ and Ca2+ supplements | [42] |
L329I | S5 | Ataxia | NA | NA | [92] |
S342I | S5 | Ataxia, dizziness, slurred speech, seizure | NA | Phenytoin effective | [93] |
V368L | S5–S6 | Severe infantile-onset dyskinesia, motor, and intellectual disability and epileptic encephalopathy | Non-functional channels | Oxcarbazepine effective | [94] |
P403S | S6 | Infantile-onset seizures and cognitive impairment in twins | NA | Lamotrigine effective in one boy; drug-resistant seizures in the other boy | [95] |
V404I | S6 | Ataxia, myokymia | Positive shift of voltage-dependent activation, slower kinetic of activation | CBZ effective | [57] |
P405L | S6 | Infantile-onset seizures and cognitive impairment | NA | ACTZ, lamotrigine and valproate effective | [95] |
P405S | S6 | Infantile-onset seizures and cognitive impairment | NA | Drug-resistant seizures | [95] |
I407M | S6 | Ataxia, dysarthria, blurred vision, hearing impairment, neuromyotonya | Non-functional channels and dominant-negative effect | NA | [85] |
V408A | S6 | Ataxia, myokymia | Faster activation and deactivation, increased C-type inactivation | NA | [49,76,87] |
V408L | S6 | Progressive cerebellar ataxia, cognitive delay, seizures, stiffness, postural abnormalities | Faster C-type inactivation | Phenytoin effective | [56] |
F414C | C-term | Ataxia, isolated photosensitive generalized tonic–clonic seizure | Nonfunctional channels and dominant-negative effect | ACTZ, oxcarbazepine, clozapam ineffective | [72] |
F414S | C-term | Ataxia, myokymia, tremors, weakness, headache, visual disturbance, nausea, slurred speech | Nonfunctional channels | Variable response to CBZ in family | [55] |
R417stop | C-term | Severe ataxia, epilepsy, periocular myokymia | Nonfunctional channels and dominant-negative effect | CBZ and ACTZ partially effective; lamotrigine, vigabatrin, clonazepam ineffective | [57,73] |
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D’Adamo, M.C.; Liantonio, A.; Rolland, J.-F.; Pessia, M.; Imbrici, P. Kv1.1 Channelopathies: Pathophysiological Mechanisms and Therapeutic Approaches. Int. J. Mol. Sci. 2020, 21, 2935. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082935
D’Adamo MC, Liantonio A, Rolland J-F, Pessia M, Imbrici P. Kv1.1 Channelopathies: Pathophysiological Mechanisms and Therapeutic Approaches. International Journal of Molecular Sciences. 2020; 21(8):2935. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082935
Chicago/Turabian StyleD’Adamo, Maria Cristina, Antonella Liantonio, Jean-Francois Rolland, Mauro Pessia, and Paola Imbrici. 2020. "Kv1.1 Channelopathies: Pathophysiological Mechanisms and Therapeutic Approaches" International Journal of Molecular Sciences 21, no. 8: 2935. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21082935