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An amino acid outside the pore region influences apamin sensitivity in small conductance Ca2+-activated K+ channels

Nolting, A; Ferraro, T; D'hoedt, D; Stocker, M; (2007) An amino acid outside the pore region influences apamin sensitivity in small conductance Ca2+-activated K+ channels. J BIOL CHEM , 282 (6) 3478 - 3486. 10.1074/jbc.M607213200. Gold open access

Abstract

Small conductance calcium-activated potassium channels (SK, K-Ca) are a family of voltage-independent K+ channels with a distinct physiology and pharmacology. The bee venom toxin apamin inhibits exclusively the three cloned SK channel subtypes (SK1, SK2, and SK3) with different affinity, highest for SK2, lowest for SK1, and intermediate for SK3 channels. The high selectivity of apamin made it a valuable toot to study the molecular makeup and function of native SK channels. Three amino acids located in the outer vestibule of the pore are of particular importance for the different apamin sensitivities of SK channels. Chimeric SK1 channels, enabling the homomeric expression of the rat SK1 (rSK1) subunit and containing the core domain (S1-S6) of rSK1, are apamin-insensitive. By contrast, channels formed by the human orthologue human SK1 (hSK1) are sensitive to apamin. This finding hinted at the involvement of regions beyond the pore as determinants of apamin sensitivity, because hSK1 and rSK1 have an identical amino acid sequence in the pore region. Here we investigated which parts of the channels outside the pore region are important for apamin sensitivity by constructing chimeras between apamin-insensitive and -sensitive SK channel subunits and by introducing point mutations. We demonstrate that a single amino acid situated in the extracellular loop between the transmembrane segments S3 and S4 has a major impact on apamin sensitivity. Our findings enabled us to convert the hSK1 channel into a channel that was as sensitive for apamin as SK2, the SK channel with the highest sensitivity.

Type: Article
Title: An amino acid outside the pore region influences apamin sensitivity in small conductance Ca2+-activated K+ channels
Open access status: An open access publication
DOI: 10.1074/jbc.M607213200
Publisher version: http://ukpmc.ac.uk/abstract/MED/17142458
Keywords: ACTIVATED POTASSIUM CHANNELS, SK CHANNELS, AFTERHYPERPOLARIZATION CURRENTS, MOLECULAR DETERMINANTS, FUNCTIONAL EXPRESSION, SYNAPTIC-TRANSMISSION, PURKINJE NEURONS, VOLTAGE-SENSOR, HEK-293 CELLS, ION CHANNELS
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/176109
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