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Filip L. A. Van Petegem, PhD
Professor and Principal Investigator of Ion Channel Lab
University of British Columbia Faculty of Medicine
PhD, Biochemistry, Ghent University
Licensee, Biochemistry, Ghent University
View Curriculum Vitae (pdf)

Mailing Address:
Vancouver, B.C.

Research Interests

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

The Van Petegem 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 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? The lab tries to answer these questions via various methods.

As ion channels are complex and dynamic proteins, The Van Petergem lab utilizes 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.

PKA and CaMKII are two key kinases that can enhance cardiac function as part of normal stress signaling. They can phosphorylate the Ryanodine Receptor, a large channel that releases calcium ions in the cytosol when stimulated. These ions then trigger contraction of the heart muscle cells. The phosphorylation facilitates calcium release. Under pathological conditions, excessive phosphorylation contributes to cardiac arrhythmia. Here the Van Petegem lab describes how exactly PKA engages the Ryanodine Receptor and found the interface to be very extensive, involving regions far outside a typical consensus sequence for PKA. The interface is the target for mutations linked to genetic forms of cardiac arrhythmia. The lab also found that phosphomimetics, and possibly phosphorylation of a nearby residue by CaMKII, can enhance the affinity of PKA for its substrate. 3D structures show that the mimetic induces secondary structure, resulting in additional interactions between substrate and PKA. The activity of one kinase thus enhances the other by affecting the substrate recognition site.

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