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Dr. Evangelia Kranias Lab

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Research Topics

Heart Failure

Cardiac Function

The Sarcoplasmic Reticulum

Phospholamban

SERCA

Calsequestrin

HRC

Junctin

HAX-1

Heat Shock Proteins

Protein Phosphate 1 Inhibitor-1

Proteomics & Phosphoproteomics

Transgenic Rabbits

Human SR Genetic Variations



Director

Calsequestrin

Calsequestrin (CSQ) is the major calcium storage protein in the SR with a binding capacity of 40-50 Ca2+ ions per molecule. SR luminal Ca2+ binds to calsequestrin during diastole to prevent Ca2+ precipitation and lower its free ionic concentration, to facilitate efficient storage. CSQ has been shown to be of major importance in the regulation of cardiac excitation-contraction coupling by our lab and others.

As shown below, CSQ forms a part of a large quaternary complex with the ryanodine receptor, triadin and junctin. These proteins are thought to each play a role in regulating calcium release through the ryanodine receptor.

Schematic representation of CSQ forming a large quaternary complex with RYR, Triadin, and Junctin.

To better understand the role of SR Ca2+ load in cardiac contractility, our lab has generated transgenic mice with cardiac overexpression of CSQ. The transgenic mice demonstrated a ten-fold increase in cardiac SR Ca2+ load, but this Ca2+ was not available for release; this resulted in diminished Ca2+ cycling, diminished myocyte fractional shortening (FS%), diminished shortening (+dL/dt) and relengthening (-dL/dt) rates, and a hypertrophic phenotype. These data demonstrate that the SR calcium load is a major determinant of cardiac contractility, and that CSQ is one of the major determinants of SR calcium load (See Figure Below).

Mutations in the CSQ gene have been shown to be associated with catecholaminergic polymorphic ventricular tachycardia (CPVT), which is believed to be induced by aberrant RyR calcium release. Thus, CSQ plays an important role in regulating RyR activity and calcium-induced calcium release. Current studies in our lab are designed to further characterize the function of CSQ in vivo to elucidate its effects on regulation of SR Ca-load, RyR Ca-release and overall Ca-cycling.

Schematic representation of the effects of CSQ overexpression in cardiac muscle.