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Biophys J, August 2000, p. 828-840, Vol. 79, No. 2
Departments of Biochemistry and Biophysics, and Molecular and Cellular Physiology, University of North Carolina, Chapel Hill, North Carolina 27599-7260 USA
We tested the hypothesis that part of the lumenal amino
acid segment between the two most C-terminal membrane segments of the
skeletal muscle ryanodine receptor (RyR1) is important for channel
activity and conductance. Eleven mutants were generated and expressed
in HEK293 cells focusing on amino acid residue I4897 homologous to the
selectivity filter of K+ channels and six other residues in
the M3-M4 lumenal loop. Mutations of amino acids not absolutely
conserved in RyRs and IP3Rs (D4903A and D4907A) showed
cellular Ca2+ release in response to caffeine,
Ca2+-dependent [3H]ryanodine binding, and
single-channel K+ and Ca2+ conductances not
significantly different from wild-type RyR1. Mutants with an I4897 to
A, L, or V or D4917 to A substitution showed a decreased single-channel
conductance, loss of high-affinity [3H]ryanodine binding
and regulation by Ca2+, and an altered caffeine-induced
Ca2+ release in intact cells. Mutant channels with amino
acid residue substitutions that are identical in the RyR and
IP3R families (D4899A, D4899R, and R4913E) exhibited a
decreased K+ conductance and showed a loss of high-affinity
[3H]ryanodine binding and loss of single-channel
pharmacology but maintained their response to caffeine in a cellular
assay. Two mutations (G4894A and D4899N) were able to maintain
pharmacological regulation both in intact cells and in vitro but had
lower single-channel K+ and Ca2+ conductances
than the wild-type channel. The results support the hypothesis that
amino acid residues in the lumenal loop region between the two most
C-terminal membrane segments constitute a part of the ion-conducting
pore of RyR1.
Biophys J, August 2000, p. 828-840, Vol. 79, No. 2
© 2000 by the Biophysical Society 0006-3495/00/08/828/13 $2.00
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