An activator of voltage- gated K+ channels Kv1.1 as a therapeutic candidate for episodic ataxia type 1

被引：8

作者：

Servettini, Ilenio ^{[1
]}

Talani, Giuseppe ^{[2
]}

Megaro, Alfredo ^{[1
]}

Setzu, Maria Dolores ^{[3
]}

Biggio, Francesca ^{[4
]}

Briffa, Michelle ^{[5
]}

Guglielmi, Luca ^{[6
]}

Savalli, Nicoletta ^{[7
]}

Binda, Francesca ^{[8
,9
]}

Delicata, Francis ^{[10
]}

Bru-Mercier, Gilles ^{[11
]}

Vassallo, Neville ^{[5
]}

Maglione, Vittorio ^{[12
]}

Cauchi, Ruben J. ^{[5
]}

Di Pardo, Alba ^{[12
]}

Collu, Maria ^{[3
]}

Imbrici, Paola ^{[13
]}

Catacuzzeno, Luigi ^{[14
]}

D'Adamo, Maria Cristina ^{[15
]}

Olcese, Riccardo ^{[7
,16
]}

Pessia, Mauro ^{[5
,11
]}

机构：

[1] Univ Perugia, Sect Physiol, Dept Med, I-06123 Perugia, Italy

[2] CNR, Inst Neurosci, I-09042 Monserrato, Italy

[3] Univ Cagliari, Dept Biomed Sci, I-09042 Monserrato, Italy

[4] Univ Cagliari, Dept Life & Environm Sci, I-09042 Monserrato, Italy

[5] Univ Malta, Fac Med & Surg, Dept Physiol & Biochem, Msida MSD 2080, Malta

[6] MRC, Lab Mol Biol, Cambridge CB2 0QH, England

[7] Univ Calif Los Angeles, David Geffen Sch Med, Dept Anesthesiol & Perioperat Med, Los Angeles, CA 90095 USA

[8] Univ Lausanne, Dept Fundamental Neurosci, CH-1011 Lausanne, Switzerland

[9] Univ Strasbourg, Inst Neurosci Cellulaires & Integrat, Ctr Natl Rech Sci, F-67000 Strasbourg, France

[10] Univ Manitoba, Rady Fac Hlth Sci, Coll Pharm, Winnipeg, MB R3E 0T5, Canada

[11] United Arab Emirates Univ, Dept Physiol, Coll Med & Hlth Sci, Al Ain 17666, U Arab Emirates

[12] Ist Ricovero & Cura Carattere Sci Neuromed, I-86077 Pozzilli, Italy

[13] Univ Bari Aldo Moro, Dept Pharm Drug Sci, I-70125 Bari, Italy

[14] Univ Perugia, Dept Chem Biol & Biotechnol, I-06123 Perugia, Italy

[15] Libera Univ Mediterranea Giuseppe DEGENNARO, Dept Med & Surg, I-70010 Casamassima, Italy

[16] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2023年 / 120卷 / 31期

关键词：

Kv1.1(KCNA1); Kv1.2(KCNA2); niflumic acid; episodic ataxia type 1; OMIM160120; NIFLUMIC ACID; POTASSIUM CHANNELS; CEREBELLAR PURKINJE; HUMAN PLASMA; LIQUID-CHROMATOGRAPHY; DEPENDENT ACTIVATION; SLOW INACTIVATION; ACTION-POTENTIALS; CALCIUM-CHANNELS; SHAKER LOCUS;

D O I：

10.1073/pnas.2207978120

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Loss-of- function mutations in the KCNA1(Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks, persistent myokymia with painful cramps in skeletal muscles, and epilepsy. Precision medicine for EA1 treatment is currently unfeasible, as no drug that can enhance the activity of Kv1.1-containing channels and offset the functional defects caused by KCNA1 mutations has been clinically approved. Here, we uncovered that niflumic acid ( NFA), a currently prescribed analgesic and anti-inflammatory drug with an excellent safety profile in the clinic, potentiates the activity of Kv1.1 channels. NFA increased Kv1.1 current amplitudes by enhancing the channel open probability, causing a hyperpolarizing shift in the voltage dependence of both channel opening and gating charge movement, slowing the OFF-gating current decay. NFA exerted similar actions on both homomeric Kv1.2 and heteromeric Kv1.1/Kv1.2 channels, which are formed in most brain structures. We show that through its potentiating action, NFA mitigated the EA1 mutation-induced functional defects in Kv1.1 and restored cerebellar synaptic transmission, Purkinje cell availability, and precision of firing. In addition, NFA ameliorated the motor performance of a knock-in mouse model of EA1 and restored the neuromuscular transmission and climbing ability in Shaker (Kv1.1) mutant Drosophila melanogaster flies (Sh5). By virtue of its multiple actions, NFA has strong potential as an efficacious single-molecule- based therapeutic agent for EA1 and serves as a valuable model for drug discovery.

引用

页数：12

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