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
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U2 - 10.1523/JNEUROSCI.3582-09.2010
DO - 10.1523/JNEUROSCI.3582-09.2010
M3 - Article
C2 - 20505092
AN - SCOPUS:77953054585
SN - 0270-6474
VL - 30
SP - 7258
EP - 7268
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 21
ER -