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Mechanism underlying activation of calcium sparks events in adult mammalian skeletal muscle

by
Andoria Tjondrokoesoemo
B. S., Rutgers University - 2005

Thesis Advisor: Jianjie Ma., Ph.D.
Graduate Program Physiology & Integrative Biology

2nd Floor Conference Room,
RWJMS-SPH building.
Piscataway

Friday, December 9, 2011
10:30 a.m.


Abstract

Functional coupling between IP3 receptor (IP3R) and ryanodine receptor (RyR) calcium channels
represents a vital aspect of intracellular calcium signaling in many cell types; however the role of this
mechanism in skeletal muscle remains elusive. Calcium sparks are the elementary units of intracellular
calcium signaling in striated muscle that appear as localized calcium release events from the sarcoplasmic
reticulum (SR) using confocal microscopy. In skeletal muscle, RyR-mediated calcium sparks are
suppressed during resting conditions, however application of transient osmotic stress can activate calcium
sparks that are restricted to the periphery of the muscle fiber. Here, I test the hypothesis that onset of these
spatially confined calcium sparks involves cross-talk from IP3R to activate RyR near the sarcolemmal
membrane. Immunostaining reveals that IP3 receptors are localized near the sarcolemma region,
coinciding with the distribution of calcium sparks in skeletal muscle. Pharmacological prevention of IP3
production or inhibition of IP3R channel activity abolishes stress-induced calcium sparks in skeletal
muscle. While genetic ablation of the type 2 IP3R does not appear to affect calcium sparks in skeletal
muscle, specific silencing of the type 1 IP3R leads to complete ablation of stress-induced calcium sparks.
Our data indicates that membrane-delimited signaling for a cross-talk between IP3R1 and RyR1
contribute to calcium spark signaling in skeletal muscle.
Maintenance of intracellular calcium homeostasis in skeletal muscle requires close association
between the tranverse (t) tubule invaginations of plasma membrane and terminal cisternae of SR. Bin1 is
a member of the amphiphysin family proteins that is associated with t-tubule membrane assembly and
remodeling. I found that silencing of Bin1 alters the t-tubule structure in adult skeletal muscle, which is
associated with reduced amplitude of calcium current and the SR calcium transient, as well as
compromised calcium sparks signaling. Our data suggest that Bin1 plays a role in the maintenance of ttubule
structure and calcium signaling in adult skeletal muscle.


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