(De)constructing the ryanodine receptor: Modeling ion permeation and selectivity of the calcium release channel

Dirk Gillespie, Le Xu, Ying Wang, Gerhard Meissner

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Abstract

Biological ion channels are proteins that passively conduct ions across membranes that are otherwise impermeable to ions. Here, we present a model of ion permeation and selectivity through a single, open ryanodine receptor (RyR) ion channel. Combining recent mutation data with electrodiffusion of finite-sized ions, the model reproduces the current/voltage curves of cardiac RyR (RyR2) in KCl, LiCl, NaCl, RbCl, CsCl, CaCl 2, MgCl 2, and their mixtures over large concentrations and applied voltage ranges. It also reproduces the reduced K + conductances and Ca 2+ selectivity of two skeletal muscle RyR (RyRl) mutants (D4899N and E4900Q). The model suggests that the selectivity filter of RyR contains the negatively charged residue D4899 that dominates the permeation and selectivity properties and gives RyR a DDDD locus similar to the EEEE locus of the L-type calcium channel. In contrast to previously applied barrier models, the current model describes RyR as a multi-ion channel with approximately three monovalent cations in the selectivity filter at all times. Reasons for the contradicting occupancy predictions are discussed. In addition, the model predicted an anomalous mole fraction effect for Na +/Cs - mixtures, which was later verified by experiment. Combining these results, the binding selectivity of RyR appears to be driven by the same charge/space competition mechanism of other highly charged channels.

LanguageEnglish (US)
Pages15598-15610
Number of pages13
JournalJournal of Physical Chemistry B
Volume109
Issue number32
DOIs
StatePublished - Aug 18 2005

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Ryanodine Receptor Calcium Release Channel
Permeation
calcium
Calcium
selectivity
Ions
ions
Ion Channels
loci
filters
skeletal muscle
Monovalent Cations
L-Type Calcium Channels
Electric potential
electric potential
mutations
Electric space charge
Muscle
space charge
Positive ions

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry

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(De)constructing the ryanodine receptor : Modeling ion permeation and selectivity of the calcium release channel. / Gillespie, Dirk; Xu, Le; Wang, Ying; Meissner, Gerhard.

In: Journal of Physical Chemistry B, Vol. 109, No. 32, 18.08.2005, p. 15598-15610.

Research output: Contribution to journalArticle

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