Modulation of K(V)4.3-KChIP2 Channels by IQM-266: Role of DPP6 and KCNE2

Autor:	Angela de Benito-Bueno, Paula G. Socuellamos, Yaiza G. Merinero, Pilar Cercos, Carolina Izquierdo, Miguel Daniel-Mozo, Irene Marín-Olivero, Angel Perez-Lara, Juan A. Gonzalez-Vera, Angel Orte, Armando Albert, Mercedes Martin-Martinez, Marta Gutierrez-Rodriguez, Carmen Valenzuela
Přispěvatelé:	Ministerio de Ciencia e Innovación (España), European Commission, Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (España)
Jazyk:	angličtina
Rok vydání:	2022
Předmět:	Organic Chemistry KChIP2 ligand DPP6 General Medicine KCNE Catalysis Computer Science Applications Inorganic Chemistry KChIP2 KV4 channels Physical and Theoretical Chemistry KChIP2 ligan Molecular Biology Spectroscopy
Zdroj:	International Journal of Molecular Sciences; Volume 23; Issue 16; Pages: 9170 International Journal of Molecular Sciences Digital.CSIC. Repositorio Institucional del CSIC instname
ISSN:	1422-0067
DOI:	10.3390/ijms23169170
Popis:	The transient outward potassium current (Itof) is generated by the activation of KV4 channels assembled with KChIP2 and other accessory subunits (DPP6 and KCNE2). To test the hypothesis that these subunits modify the channel pharmacology, we analyzed the electrophysiological effects of (3-(2-(3-phenoxyphenyl)acetamido)-2-naphthoic acid) (IQM-266), a new KChIP2 ligand, on the currents generated by KV4.3/KChIP2, KV4.3/KChIP2/DPP6 and KV4.3/KChIP2/KCNE2 channels. CHO cells were transiently transfected with cDNAs codifying for different proteins (KV4.3/KChIP2, KV4.3/KChIP2/DPP6 or KV4.3/KChIP2/KCNE2), and the potassium currents were recorded using the whole-cell patch-clamp technique. IQM-266 decreased the maximum peak of KV4.3/KChIP2, KV4.3/KChIP2/DPP6 and KV4.3/KChIP2/KCNE2 currents, slowing their time course of inactivation in a concentration-, voltage-, time- and use-dependent manner. IQM-266 produced an increase in the charge in KV4.3/KChIP2 channels that was intensified when DPP6 was present and abolished in the presence of KCNE2. IQM-266 induced an activation unblocking effect during the application of trains of pulses to cells expressing KV4.3/KChIP2 and KV4.3/KChIP2/KCNE2, but not in KV4.3/KChIP2/DPP6 channels. Overall, all these results are consistent with a preferential IQM-266 binding to an active closed state of Kv4.3/KChIP2 and Kv4.3/KChIP2/KCNE2 channels, whereas in the presence of DPP6, IQM-266 binds preferentially to an inactivated state. In conclusion, DPP6 and KCNE2 modify the pharmacological response of KV4.3/KChIP2 channels to IQM-266. MCIN/AEI SAF2016-75021-R RTI2018-097189-B-C22 BIO2017-89523-R PID2019-104366RB-C21 PID2019-104366RB-C22 PID2020-114256RB-I00 PID2020-119805RB-I00 BES-2017-080184 BES-2010-036573 PRE2018-083280 RYC2018-023837-I ERDF A way of making Europe SAF2016-75021-R RTI2018-097189-B-C22 BIO2017-89523-R FEDER/Junta de Andalucia-Consejeria de Transformacion Economica, Industria, Conocimiento A-FQM-386-UGR20 Instituto de Salud Carlos III CIBERCV CB/11/00222 Consejo Superior de Investigaciones Cientificas PIE202180E073 PIE201820E104 2019AEP148 ESF Investing in your future BES-2017-080184 BES-2010-036573 PRE2018-083280 RYC2018-023837-I Instituto de Salud Carlos III Spanish Government European Commission FPU17/02731
Databáze:	OpenAIRE
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