The therapeutic mode of action of 4-aminopyridine in cerebellar ataxia

Karina Alviña, Kamran Khodakhah

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Episodic ataxia type 2 (EA2) is a hereditary cerebellar ataxia associated with mutations in the P/Q-type voltage-gated calcium (Ca2+) channels. Therapeutic approaches for treatment of EA2 are very limited. Presently, the potassium (K+) channel blocker 4-aminopyridine (4-AP) constitutes the most promising treatment, although its mechanism of action is not understood. Here we show that, in contrast to what is commonly believed, therapeutic concentrations of 4-AP do not increase the inhibitory drive of cerebellar Purkinje cells. Instead, 4-AP restores the severely diminished precision of pacemaking in Purkinje cells of EA2 mutant mice by prolonging the action potential and increasing the action potential afterhyperpolarization. Consistent with this mode of action, the therapeutic efficacy of 4-AP was comparable, and not additive, to chlorzoxazone, an activator of Ca2+-dependent K +channels that also restores the precision of Purkinje cell pacemaking. The likely target of 4-AP at the concentrations used are the K v1 family of K+ channels, possibly the Kv1.5 subtype. Because at higher concentrations 4-AP blocks a large array of K + channels and is a proconvulsant, use of selective Kv1 channel blockers is likely to be a safer substitute for treatment of cerebellar ataxia. Copyright

Original languageEnglish (US)
Pages (from-to)7258-7268
Number of pages11
JournalJournal of Neuroscience
Volume30
Issue number21
DOIs
StatePublished - May 26 2010

Fingerprint

Cerebellar Ataxia
4-Aminopyridine
Purkinje Cells
Action Potentials
Therapeutics
Chlorzoxazone
Potassium Channel Blockers
Spinocerebellar Degenerations
Calcium Channels
Mutation
Type 2 Episodic Ataxia

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

The therapeutic mode of action of 4-aminopyridine in cerebellar ataxia. / Alviña, Karina; Khodakhah, Kamran.

In: Journal of Neuroscience, Vol. 30, No. 21, 26.05.2010, p. 7258-7268.

Research output: Contribution to journalArticle

@article{450d49ae3f21462b917569ed216c279d,
title = "The therapeutic mode of action of 4-aminopyridine in cerebellar ataxia",
abstract = "Episodic ataxia type 2 (EA2) is a hereditary cerebellar ataxia associated with mutations in the P/Q-type voltage-gated calcium (Ca2+) channels. Therapeutic approaches for treatment of EA2 are very limited. Presently, the potassium (K+) channel blocker 4-aminopyridine (4-AP) constitutes the most promising treatment, although its mechanism of action is not understood. Here we show that, in contrast to what is commonly believed, therapeutic concentrations of 4-AP do not increase the inhibitory drive of cerebellar Purkinje cells. Instead, 4-AP restores the severely diminished precision of pacemaking in Purkinje cells of EA2 mutant mice by prolonging the action potential and increasing the action potential afterhyperpolarization. Consistent with this mode of action, the therapeutic efficacy of 4-AP was comparable, and not additive, to chlorzoxazone, an activator of Ca2+-dependent K +channels that also restores the precision of Purkinje cell pacemaking. The likely target of 4-AP at the concentrations used are the K v1 family of K+ channels, possibly the Kv1.5 subtype. Because at higher concentrations 4-AP blocks a large array of K + channels and is a proconvulsant, use of selective Kv1 channel blockers is likely to be a safer substitute for treatment of cerebellar ataxia. Copyright",
author = "Karina Alvi{\~n}a and Kamran Khodakhah",
year = "2010",
month = "5",
day = "26",
doi = "10.1523/JNEUROSCI.3582-09.2010",
language = "English (US)",
volume = "30",
pages = "7258--7268",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "21",

}

TY - JOUR

T1 - The therapeutic mode of action of 4-aminopyridine in cerebellar ataxia

AU - Alviña, Karina

AU - Khodakhah, Kamran

PY - 2010/5/26

Y1 - 2010/5/26

N2 - Episodic ataxia type 2 (EA2) is a hereditary cerebellar ataxia associated with mutations in the P/Q-type voltage-gated calcium (Ca2+) channels. Therapeutic approaches for treatment of EA2 are very limited. Presently, the potassium (K+) channel blocker 4-aminopyridine (4-AP) constitutes the most promising treatment, although its mechanism of action is not understood. Here we show that, in contrast to what is commonly believed, therapeutic concentrations of 4-AP do not increase the inhibitory drive of cerebellar Purkinje cells. Instead, 4-AP restores the severely diminished precision of pacemaking in Purkinje cells of EA2 mutant mice by prolonging the action potential and increasing the action potential afterhyperpolarization. Consistent with this mode of action, the therapeutic efficacy of 4-AP was comparable, and not additive, to chlorzoxazone, an activator of Ca2+-dependent K +channels that also restores the precision of Purkinje cell pacemaking. The likely target of 4-AP at the concentrations used are the K v1 family of K+ channels, possibly the Kv1.5 subtype. Because at higher concentrations 4-AP blocks a large array of K + channels and is a proconvulsant, use of selective Kv1 channel blockers is likely to be a safer substitute for treatment of cerebellar ataxia. Copyright

AB - Episodic ataxia type 2 (EA2) is a hereditary cerebellar ataxia associated with mutations in the P/Q-type voltage-gated calcium (Ca2+) channels. Therapeutic approaches for treatment of EA2 are very limited. Presently, the potassium (K+) channel blocker 4-aminopyridine (4-AP) constitutes the most promising treatment, although its mechanism of action is not understood. Here we show that, in contrast to what is commonly believed, therapeutic concentrations of 4-AP do not increase the inhibitory drive of cerebellar Purkinje cells. Instead, 4-AP restores the severely diminished precision of pacemaking in Purkinje cells of EA2 mutant mice by prolonging the action potential and increasing the action potential afterhyperpolarization. Consistent with this mode of action, the therapeutic efficacy of 4-AP was comparable, and not additive, to chlorzoxazone, an activator of Ca2+-dependent K +channels that also restores the precision of Purkinje cell pacemaking. The likely target of 4-AP at the concentrations used are the K v1 family of K+ channels, possibly the Kv1.5 subtype. Because at higher concentrations 4-AP blocks a large array of K + channels and is a proconvulsant, use of selective Kv1 channel blockers is likely to be a safer substitute for treatment of cerebellar ataxia. Copyright

UR - http://www.scopus.com/inward/record.url?scp=77953054585&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953054585&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.3582-09.2010

DO - 10.1523/JNEUROSCI.3582-09.2010

M3 - Article

VL - 30

SP - 7258

EP - 7268

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 21

ER -