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Effects of CL888 on Kv4.3, Kv4.3/KChip2c and Kv4.3/KChiP3 channels

AuthorsPrieto, Ángela ; Cercós, Pilar ; Cruz, Alicia de la ; González, Teresa ; Gutiérrez-Rodríguez, Marta ; Naranjo, José Ramón; Valenzuela, Carmen
Issue Date2014
Citation58th Annual Meeting of the Biophysical Society (2014)
AbstractKv4.3 generates the transient outward current that plays an essential role in shaping the early phase of the cardiac action potential. These channels are regulated by a family of calcium-binding proteins called KChIPs. Four members of this family have been cloned. KChIP3 and KChIP2c bind to Kv4.3 in the endoplasmic reticulum and facilitate trafficking to the membrane and regulate the channel gating. CL888 induces alteration or disruption in the binding between KChIP1 and Kv4.3, modulating the function of the complex. The aim of our study was to determine the effects of CL888 on Kv4.3/KChIP3 and Kv4.3/KChIP2 complex, as well as on Kv4.3 alone. KChIP3, KChiP2 and Kv4.3 channels were expressed in CHO cells. Currents were recorded using the whole-cell patch-clamp technique. Block of Kv4.3/KChIP3 channels induced by CL888 was concentration dependent with an IC50 of 23 nM, whereas Kv4.3 and Kv4.3/KChIP2c was not. At 100 nM, degree of block ranged according to: Kv4.3/KChIP3>Kv4.3/KChIP2c>Kv4.3. In all 3 channel complexes, CL888 accelerated the inactivation kinetics of the current by decreasing the slow time constant (τs). Thus, for Kv4.3/KChIP3 the τs value changed from 20.6±1.6 ms to 17.0±1.5 ms (n=5, P<0.05); for Kv4.3, from 19.7±1.6 ms to 10.8±1.5 ms (n=4, P<0.05); and for Kv4.3/KChIP2, from 38.1±5.8 ms to 23.9±4.0 ms (n=5, P<0.05). CL888 did not affect the voltage dependency of steady-state inactivation of Kv4.3/KChIP3 channels. However, it accelerated their recovery from inactivation kinetics (τre=62.0±12.1 ms vs. 49.8±9.8 ms, n=6, P<0.05). We conclude that CL888 binds to Kv4.3 channels and modulates the gating and the kinetics of these channels. However, Kv4.3/KChIP3 complex results to be more sensitive than Kv4.3 and Kv4.3/KChIP2c. Therefore, the sensitivity of Kv4.3 channels to CL888-like drugs will vary depending of the associated regulatory subunits.
DescriptionResumen del póster presentado al 58th Annual Meeting of the Biophysical Society, celebrado en San Francisco-California (US) del 15 al 19 de febrero de 2014.
Appears in Collections:(IIBM) Comunicaciones congresos
(IQM) Comunicaciones congresos
(CNB) Comunicaciones congresos
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