Allosteric effects of external K(+) ions mediated by the aspartate of the GYGD signature sequence in the Kv2.1 K(+) channel.
K(+) channels achieve exquisite ion selectivity without jeopardizing efficient permeation by employing multiple, interacting K(+)-binding sites. Introduction of a cadmium (Cd(2+))-binding site in the external vestibule of Kv2.1 (drk1), allowed us to functionally characterize a binding site for external monovalent cations. Permeant ions displayed higher affinity for this site than non-permeant monovalent cations, although the selectivity profile was different from that of the channel. Point mutations identified the highly conserved aspartate residue immediately following the selectivity filter as a critical determinant of the antagonism between external K(+) and Cd(2+) ions. A conservative mutation at this position (D378E) significantly affected the open-state stability. Moreover, the mean open time was found to be modulated by external K(+) concentration, suggesting a coupling between channel closing and the permeation process. Reducing the Rb(+) conductance by mutating the selectivity filter to the sequence found in Kv4.1, also significantly reduced the effectiveness of Rb(+) ions to antagonize Cd(2+) inhibition, thereby implicating the selectivity filter as the site at which K(+) ions exert their antagonistic effect on Cd(2+) block. The equivalent of D378 in KcsA, D80, takes part in an inter-subunit hydrogen-bond network that allows D80 to functionally interact with the selectivity filter. The results suggest that external K(+) ions antagonize Cd(2+) inhibition (in I379C) and modulate the mean open time (in the wild-type Kv2.1) by altering the occupancy profile of the K(+)-binding sites in the selectivity filter.[1]References
- Allosteric effects of external K(+) ions mediated by the aspartate of the GYGD signature sequence in the Kv2.1 K(+) channel. Chapman, M.L., Blanke, M.L., Krovetz, H.S., Vandongen, A.M. Pflugers Arch. (2006) [Pubmed]
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