Allosteric effects of external K+ ions mediated by the aspartate of the GYGD signature sequence in the Kv2.1 K+ channel.

Loading...
Thumbnail Image

Date

2006-03

Authors

Chapman, Mark L
Blanke, Marie L
Krovetz, Howard S
VanDongen, Antonius MJ

Journal Title

Journal ISSN

Volume Title

Citation Stats

Abstract

K+ channels achieve exquisite ion selectivity without jeopardizing efficient permeation by employing multiple, interacting K+-binding sites. Introduction ofa cadmium (Cd2+)-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 Cd2+ 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 inKv4.1, also significantly reduced the effectiveness ofRb+ ions to antagonize Cd2+ inhibition, thereby implicating the selectivity filter as the site at which K+ions exert their antagonistic effect on Cd2+ block. The equivalent of D378 in KcsA, D80, takes part in an inter-subunit hydrogen-bond network that allows D80to functionally interact with the selectivity filter. The results suggest that external K+ ions antagonize Cd2+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.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1007/s00424-005-1515-2

Publication Info

Chapman, Mark L, Marie L Blanke, Howard S Krovetz and Antonius MJ VanDongen (2006). Allosteric effects of external K+ ions mediated by the aspartate of the GYGD signature sequence in the Kv2.1 K+ channel. Pflugers Archiv : European journal of physiology, 451(6). pp. 776–792. 10.1007/s00424-005-1515-2 Retrieved from https://hdl.handle.net/10161/30440.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

VanDongen

Antonius M. J. VanDongen

Associate Professor of Pharmacology & Cancer Biology

We have discovered a new connection between the memory gene Arc (Activity Regulated, Cytoskeletal-associated protein) and Alzheimer's disease. Arc is a master regulator of of synaptic plasticity and epigenetically controls the transcription of 1900 genes associated with with synaptic function, neuronal plasticity, intrinsic excitability (channels, receptors, transporters), and signaling pathways (transcription factors/regulators). Approximately 100 genes whose activity-dependent expression level depends on Arc are associated with the pathophysiology of Alzheimer’s disease, suggesting a critical role for Arc in the development of neurodegenerative disorders.


Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.