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. They are essential for neuronal signaling, the beating of our hearts, the contraction of muscle, and much more. 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. How do the ion channels gate? How do auxiliary proteins, small molecules, and post-translational modifications change their behavior? How do they assemble into larger complexes? How do disease-associated mutation change their function? We try to answer these questions via various methods.

 

As ion channels are complex and dynamic proteins, we utilize a combination of techniques to study their behaviour. This includes X-ray crystallography and cryo-electron microscopy to study their 3D structures, and electrophysiology to measure the electrical currents generated when the channels open.

 

Recent paper: Wang K, Holt C, Lu J, Brohus M, Larsen KT, Overgaard MT, Wimmer R, Van Petegem F (2018)Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel. PNAS 115:E10556-E10565.

 

 

Calmodulin is a ubiquitous Ca2+ sensing protein that can bind >100 different targets. The human genome encodes three CALM genes that encode identical proteins. Being one of the most conserved proteins known, it was long thought that any mutation in Calmodulin would be embryonically lethal. However, several reports have recently described patients with severe cardiac arrhythmia, due to a mutation in one of their CALM genes. We solved high-resolution structures of several disease mutants, and analyze these in the context of their binding to L-type Calcium channels (CaV1.2). The latter channels undergo calcium-dependent inactivation (CDI), a phenomenon whereby the electrical currents through this channel rapidly decrease. This is critical for shaping the proper cardiac action potential.. As CDI mediated by Calmodulin, the mutations directly interfere with the process, giving rise to Long-QT syndrome, a type of inherited arrhythmia. We found that several mutations have different inherent mechanisms to affect CDI. Two of them cause a novel, pathological conformation that changes the binding mode to the IQ domain of CaV1.2. Another one causes a small distortion that reduced the affinity for calcium. A fourth mutant, however, leaves the Calcium-bound form nearly unperturbed, but changes the conformation of Calcium-free calmodulin, in turn changing the interaction with the IQ domain. The study highlights the unusual plasticity of Calmodulin, and that different mutations, despite similar functional outcomes, can use very different mechanisms to cause disease. More info can be found here.

 

This project is in collaboration with the labs of Michael Overgaard and Reinhard Wimmer (Aalborg University, Denmark)

 

 

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: Nov 2018