Abstract
Calsequestrin, the major calcium sequestering protein in the sarcoplasmic
reticulum of muscle, forms a quaternary complex with the ryanodine
receptor calcium release channel and the intrinsic membrane proteins
triadin and junctin. We have investigated the possibility that calsequestrin
is a luminal calcium concentration sensor for the ryanodine receptor.
We measured the luminal calcium concentration at which calsequestrin
dissociates from the ryanodine receptor and the effect of calsequestrin
on the response of the ryanodine receptor to changes in luminal calcium.
We provide electrophysiological and biochemical evidence that: 1),
luminal calcium concentration of >/=4 mM dissociates calsequestrin
from junctional face membrane, whereas in the range of 1-3 mM calsequestrin
remains attached; 2), the association with calsequestrin inhibits
ryanodine receptor activity, but amplifies its response to changes
in luminal calcium concentration; and 3), under physiological calcium
conditions (1 mM), phosphorylation of calsequestrin does not alter
its ability to inhibit native ryanodine receptor activity when the
anchoring proteins triadin and junctin are present. These data suggest
that the quaternary complex is intact in vivo, and provides further
evidence that calsequestrin is involved in the sarcoplasmic reticulum
calcium signaling pathway and has a role as a luminal calcium sensor
for the ryanodine receptor.
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