University of Waterloo biologists have discovered how an outer shield over T-type channels change the electrochemical signaling of heart and brain cells. Understanding how these shields work will help researchers eventually develop a new class of drugs for treating epilepsy, cardiovascular disease and cancer.
The study published in the Journal of Biological Chemistry was selected as the “Paper of the Week” for its significance.
Waterloo Biology graduate students Adriano Senatore, Wendy Guan and Research Associate Adrienne Boone carried out the research under the supervision of Professor David Spafford.
The biologists discovered T-type channels in the pond snail, Lymnaea stagnalis, can shift from using calcium ions to using sodium ions to generate the electrical signal because of an outer shield of amino acids called a turret situated above the channel’s entrance.
Low voltage T-type channels generate tiny pulses of current at regular intervals by selectively passing positively charged cations across the cell’s membrane through a gate-like channel. The channels are normally extremely selective, allowing only one sodium ion to pass for every 10,000 calcium ions.
The resulting rhythmic signals produced by this transfer of cations are what support the synchronous contraction of our heart muscles and neuronal firing in parts of the brain, like the thalamus, which helps regulate our sleep-wake cycle, or circadian rhythm.
In addition to their published findings, the researchers also found the shield-like turrets in pond snails restrict access of therapeutic drugs to the channel.
T-type channels in pond snails and other invertebrates are similar to those found in humans. Although pond snails reach only 7 cm in length, its simple neural network and physiology make it a popular model organism with neurobiologists.
Over-active T-type channels have been linked to epilepsy, cardiac problems, neuropathic pain, as well as the spreading of several kinds of cancer have been linked to. Drugs that could quench out-of-control T-type channel activity are unable to bind to the channels themselves.
We wanted to understand the molecular structures of T-type channels,” said Spafford. “How they pass ionic currents to generate electrical activity, and to identify drug binding sites, and the drugs which may block these channels to treat neurological disease or heart complications.”
The group is currently investigating how dismantling this turret will improve drug access and binding in T-type channels.
Adriano Senatore recently graduated with his doctorate in 2013. He received the Governor General’s Medal for best PhD thesis at the University of Waterloo. Senatore has published more than a dozen research articles with Prof. Spafford for his PhD thesis research.
This work was funded by the Heart and Stroke Foundation of Canada and the NSERC Discovery program.