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A role for the middle C terminus of G-protein-activated inward rectifier potassium channels in regulating gating. Paper-9282027. There was no effect on single-channel conductance.
This glutamate is conserved in all members of the Kir family. Paper-9282027.
The effect of modification was dependent on the charge of the reagent.
Thus it is unlikely that these cysteines line the permeation pathway of the open pore.
Our results suggest that this residue regulates channel gating through an electrostatic mechanism.
With the exception of GIRK2C65, these cysteines were relatively inaccessible to large modifying reagents.
Thus a switch in charge at this middle C-terminal position was sufficient to gate the channel open and closed.
Cysteines introduced 3 and 6 amino acids upstream of GIRK2C321 (G318C and E315C) were considerably more accessible.
The accessibility was further reduced by a mutation at the end of the second transmembrane domain that stabilized the open state of the channel.
We have used sulfhydryl-modifying reagents to investigate the regulation of G-protein- activated inward rectifier potassium ( GIRK) channels via their cytoplasmic domains. Paper-9282027.
Modification of either the conserved N-terminal cysteines (GIRK1C53 and GIRK2C65) or the middle C-terminal cysteines (GIRK1C310 and GIRK2C321) independently inhibited GIRK1/ GIRK2 heteromeric channels. Paper-9282027.
Modification of E315C in GIRK2 and E304C in GIRK1 by sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES(-)) increased the current by approximately 17-fold, whereas modification by 2-aminoethyl methanethiosulfonate hydrochloride (MTSEA(+)), abolished the current. Paper-9282027.
The E303K mutation in Kir2.1 inhibits channel function and causes Andersen's syndrome in humans (Plaster, N. M., Tawil, R., Tristani-Firouzi, M., Canun, S., Bendahhou, S., Tsunoda, A., Donaldson, M. R., Iannaccone, S. T., Brunt, E., Barohn, R., Clark, J., Deymeer, F., George, A. L., Jr., Fish, F. A., Hahn, A., Nitu, A., Ozdemir, C., Serdaroglu, P., Subramony, S. H., Wolfe, G., Fu, Y. H., and Ptacek, L. J. (2001) Cell 105, 511-519 and Preisig-Muller, R., Schlichthorl, G., Goerge, T., Heinen, S., Bruggemann, A., Rajan, S., Derst, C., Veh, R. W., and Daut, J. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 7774-7779). Paper-9282027.
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