Voltage-gated Ca2+ channels select Ca2+ over competing, more abundant ions by means of a high affinity binding site in the pore. The maximum off rate from this site is ∼1,000× slower than observed Ca2+ current. Various theories that explain how high Ca2+ current can pass through such a sticky pore all assume that flux occurs from a condition in which the pore's affinity for Ca2+ transiently decreases because of ion interactions. Here, we use rate theory calculations to demonstrate a different mechanism that requires no transient changes in affinity to quantitatively reproduce observed Ca2+ channel behavior. The model pore has a single high affinity Ca2+ binding site flanked by a low affinity site on either side; ions permeate in single file without repulsive interactions. The low affinity sites provide steps of potential energy that speed the exit of a Ca2+ ion off the selectivity site, just as potential energy steps accelerate other chemical reactions. The steps could be provided by weak binding in the nonselective vestibules that appear to be a general feature of ion channels, by specific protein structures in a long pore, or by stepwise rehydration of a permeating ion. The previous ion-interaction models and this stepwise permeation model demonstrate two general mechanisms, which might well work together, to simultaneously generate high flux and high selectivity in single file pores.
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1 February 1998
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February 01 1998
Ion Channel Selectivity through Stepwise Changes in Binding Affinity
Thieu X. Dang,
Thieu X. Dang
From the Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201-3098
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Edwin W. McCleskey
Edwin W. McCleskey
From the Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201-3098
Search for other works by this author on:
Thieu X. Dang
From the Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201-3098
Edwin W. McCleskey
From the Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201-3098
Address correspondence to Ed McCleskey, Vollum Institute L-474, O.H.S.U., Portland, OR 97201-3098. Fax: 503-494-6972; E-mail: [email protected]
Permeation programs are available online at http://www.ohsu.edu/vollum/mccleskey/
Thieu X. Dang's present address is Hewlett-Packard Co., Camas, WA 98607.
Received:
August 25 1997
Accepted:
November 12 1997
Online ISSN: 1540-7748
Print ISSN: 0022-1295
1998
J Gen Physiol (1998) 111 (2): 185–193.
Article history
Received:
August 25 1997
Accepted:
November 12 1997
Citation
Thieu X. Dang, Edwin W. McCleskey; Ion Channel Selectivity through Stepwise Changes in Binding Affinity . J Gen Physiol 1 February 1998; 111 (2): 185–193. doi: https://doi.org/10.1085/jgp.111.2.185
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