Ion channel function, structure and regulation in health and disease

In the Pantazis Laboratory of Cellular Excitability - PaLaCE, we employ cutting-edge experimental and computational approaches to understand how the intricate structure of ion channels relates to their function.

We also study how protein partners and signaling molecules regulate ion channel activity, altering their structure and bestowing new functional properties.

Finally, we are striving to understand, at the molecular level, life-threatening diseases that arise from ion channel dysfunction (channelopathies).

We use techniques such as electrophysiology, fluorescence spectroscopy, confocal microscopy, flow cytometry, and computer simulation—in addition, we develop new methods to tackle experimental challenges in physiology.

1) Molecular physiology and regulation of presynaptic voltage-gated calcium channels

Calcium channel (CaV) activation is the first molecular event that occurs when an action potential (AP) arrives to the presynaptic terminal, and it culminates in neurotransmitter release. Yet, while AP propagation and transmitter release are relatively well-studied processes, presynaptic CaVs remain “black boxes”—albeit with beautifully intricate atomic structures!

We combine the ultra-fast COVG voltage-clamp with voltage-clamp fluorometry, to optically track how the dynamic structure of human presynaptic calcium channels responds to electrical signals, and how these responses (hence synaptic transmission) are affected by chronic depolarization and second messengers. Our aim is to reveal the operation of these fascinating molecular machines, and bridge the gap in knowledge between electrical and neurotransmitter signaling.

2) Molecular etiology of excitopathies

At the molecular level, electrical signaling in neurons and muscle cells is remarkably similar: both cell types use sodium channels to amplify electrical signals, potassium channels to terminate them, and calcium channels to convert electrical signals to an output function: secrete neurotransmitter or contract. We study all aforementioned channel types and how they contribute to diseases of electrical excitability, “excitopathies”. We are currently investigating the role of novel potassium-channel variants in epilepsy, calcium channels in psychiatric disorders and the cardiac sodium channel in a case of familial arrhythmia. We are interested in how disease-causing mutations affect the complex function of ion channels and the cells that harbor them, and how mutant channel subunits are synthesized and handled by the cell.