TY - JOUR
T1 - An activator of voltage-gated K+ channels Kv1.1 as a therapeutic candidate for episodic ataxia type 1
AU - Servettini, Ilenio
AU - Talani, Giuseppe
AU - Megaro, Alfredo
AU - Setzu, Maria Dolores
AU - Biggio, Francesca
AU - Briffa, Michelle
AU - Guglielmi, Luca
AU - Savalli, Nicoletta
AU - Binda, Francesca
AU - Delicata, Francis
AU - Bru-Mercier, Gilles
AU - Vassallo, Neville
AU - Maglione, Vittorio
AU - Cauchi, Ruben J.
AU - Pardo, Alba Di
AU - Collu, Maria
AU - Imbrici, Paola
AU - Catacuzzeno, Luigi
AU - D’Adamo, Maria Cristina
AU - Olcese, Riccardo
AU - Pessia, Mauro
N1 - Funding Information:
N.V.), NIH/NIGMS R35GM131896 (to R.O.), and the American Heart Association Postdoctoral Fellowship 14POST18780018 (to N.S.).
Funding Information:
ACKNOWLEDGMENTS. We would like to thank Prof. John P. Adelman and Prof. James Maylie for sharing the Kv1.1V408A/+ mice with us. We are grateful to Dr. Massimo Pierucci for providing the Spike2 script and Francesco Pessia for data analysis. We thank Dr. Raffaele Grandi and the drafters from Edi.Ermes Medical Publisher (Milan, Italy; https://www.ediermes.com/) for providing excellent artwork. We also thank Prof. Jean-Yves Chatton, Dr. Balaji Venkataraman, Dr. Richardjayaraj Lawrencejayaraj, Dr. Manigandan Krishnan, and Dr. Elisabetta Batzu for their contributions to this work. This study was supported by United Arab Emirates University grants no. 31M468, 31M452, 21M149-AARE20-260 and MCST R&I-2017-029T BooKind (to M.P.), MCST R&I-2008-068 (to R.J.C. and
Publisher Copyright:
Copyright © 2023 the Author(s).
PY - 2023/8/1
Y1 - 2023/8/1
N2 - 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.
AB - 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.
KW - Kv1.1(KCNA1)
KW - Kv1.2(KCNA2)
KW - OMIM160120
KW - episodic ataxia type 1
KW - niflumic acid
UR - http://www.scopus.com/inward/record.url?scp=85165777081&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85165777081&partnerID=8YFLogxK
U2 - 10.1073/pnas.2207978120
DO - 10.1073/pnas.2207978120
M3 - Article
C2 - 37487086
AN - SCOPUS:85165777081
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 31
M1 - e2207978120
ER -