Pharmacological reports : PR · 2015
The molecular basis of chloroethylclonidine block of inward rectifier (Kir2.1 and Kir4.1) K(+) channels.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Rodríguez-Menchaca Aldo A, Aréchiga-Figueroa Ivan A, Sánchez-Chapula José A
Аннотация
BACKGROUND: Inwardly rectifying potassium (Kir) channels are expressed in many cell types and contribute to a wide range of physiological processes. Kir channels dysfunction cause several diseases in brain, ear, heart, muscle, kidney and pancreas, and developmental abnormalities. Therefore, a better understanding of Kir channels pharmacology is desirable. In this study we characterized the electrophysiological and molecular basis of the inhibition produced by the α-adrenergic agonist/antagonist chloroethylclonidine of the currents generated by wild type and mutant Kir2.1 and Kir4.1 channels heterologously expressed in HEK293 cells.
METHODS: Macroscopic currents were recorded using the patch clamp technique in the inside out configuration.
RESULTS: We found that chloroethylclonidine inhibits the Kir2.1 and Kir4.1 channels in a voltage-dependent manner by interacting with pore facing residues in the cytoplasmic and transmembrane domains, respectively. Site-directed mutagenesis experiments demonstrate that chloroethylclonidine interact with Kir2.1 channels in the cytoplasmic pore involving the E224, E299, D255 and D259 residues, whereas in Kir4.1channels T128 and E158 residues located in the transmembrane pore are important for the chloroethylclonidine effect.
CONCLUSIONS: Overall, our results suggest that differences in the cavity of Kir channels are determinants in its interactions with chloroethylclonidine.
METHODS: Macroscopic currents were recorded using the patch clamp technique in the inside out configuration.
RESULTS: We found that chloroethylclonidine inhibits the Kir2.1 and Kir4.1 channels in a voltage-dependent manner by interacting with pore facing residues in the cytoplasmic and transmembrane domains, respectively. Site-directed mutagenesis experiments demonstrate that chloroethylclonidine interact with Kir2.1 channels in the cytoplasmic pore involving the E224, E299, D255 and D259 residues, whereas in Kir4.1channels T128 and E158 residues located in the transmembrane pore are important for the chloroethylclonidine effect.
CONCLUSIONS: Overall, our results suggest that differences in the cavity of Kir channels are determinants in its interactions with chloroethylclonidine.