From Cardiac arrhythmia to epilepsy - Ion channels in health and disease

Our lab studies the structure and function of ion channels, membrane protein responsible for electrical signaling in excitable cells. Ion channel genes are targeted by hundreds of genetic variants that result in 'channelopathies', a set of severe disorders ranging from inherited cardiac arrhythmias to chronic pain and congenital epilepsy.

 

We use a combination of structural biology (cryo-electron microscopy, X-ray crystallography) and electrophysiology.

 

Highlighted paper: Wong King Yuen S, Campiglio M, Tung CC, Flucher BE, Van Petegem F (2017) Structural insights into binding of STAC proteins to voltage-gated calcium channels. PNAS In Press.

 
 

 

 

 

Skeletal muscle contraction is a tightly orchestrated event that starts with the depolarization of the T-tubular membrane.  At the centre is a functional and mechanical coupling between two membrane proteins: L-type voltage-gated calcium channels, located in the plasma membrane, and Ryanodine Receptors, located in the membrane of the sarcoplasmic reticulum. How exactly these proteins associate has remained a mystery, but recent reports have highlighted a key role for the STAC3 adaptor protein in this process.  Here we provide the first structural snapshots of the three STAC isoforms, and identify a cytosolic loop of two CaV isoforms as a functional interaction site.  A mutation linked to Native American Myopathy is at the interface and abolishes the interaction. This results in a decreased efficiency of excitation-contraction coupling.

 

Excitation-contraction coupling experiments were performed by Martha Campiglio and Bernhard Flucher (University of Innsbruck)

 

 

keywords: cardiac arrhythmia, epilepsy, ion channel, CPVT, Dravet syndrome, malignant hyperthermia, central core disease, excitation-contraction coupling, ryanodine receptor, sodium channel, calcium channel, voltage-gated sodium channel, calmodulin, X-ray crystallography, ryanodine, RyR, RyR1, RyR2, RyR3, high resolution, structure, arrhythmia, genetic disorder, ITC, isothermal titration calorimetry, Brugada syndrome, Long QT syndrome, arrhythmia, channel, electrophysiology, GEFS+, Native American Myopathy, cryo-EM, Vancouver, UBC, Biochemistry, Canada
tel:604.827.4267 | email:filip.vanpetegem'at'gmail.com

Van Petegem Lab © 2007, updated: Oct 2017