Posts tagged potassium channel
Articles and news from the latest research reports.
Tarantula Toxin is Used to Report on Electrical Activity in Live Cells
Crucial experiments to develop a novel probe of cellular electrical activity were conducted in the Neurobiology course at the Marine Biological Laboratory (MBL) in 2013. Today, that optical probe, which combines a tarantula toxin with a fluorescent compound, is introduced in a paper in the Proceedings of the National Academy of Sciences.
The lead authors of the paper are Drew C. Tilley of University of California-Davis and the late Kenneth Eum, who was a teaching assistant in the Neurobiology course and a Ph.D. candidate at UC-Davis.
The probe takes advantage of the potent ability of tarantula toxin to bind to electrically active cells, such as neurons, while the cells are in a resting state. The team discovered that a trace amount of toxin combined with a fluorescent compound would bind to a specific subset of voltage-activated proteins (Kv2-type potassium ion channels) in live cells. The probe lights up cell surfaces with this ion channel, and the fluorescent signal dims when the channel is activated by electrical signals.
This is the first time that researchers have been able to visually observe these ion channels “turning on” without first genetically modifying them. All that is required is a means to detect probe location, suggesting that related probes could potentially one day be used to map neural activity in the human brain.
“This is a demonstration, a prototype probe. But the promise is that we could use it to measure the activity state of the electrical system in an organism that has not been genetically compromised,” says senior author Jon Sack, an assistant professor in the departments of Physiology and Membrane Biology at UC-Davis. Sack is a faculty member in the MBL Neurobiology course.
Since the probe binds selectively to one of the many different kinds of ion channels, it can help scientists disentangle the function of those specific channels in neuronal signaling. This can, in turn, lead to the identification of drug targets for neurological diseases and disorders.
“We have an incredible diversity of ion channels, and even of voltage-activated ion channels. The real trouble has been determining which ones perform which roles. Which ones turn on and when in normal nervous system functioning? Which are involved in abnormal states or syndromes?” Sack says. “The dream is to be able to see what the different types of ion channels are doing and when, to understand what they contribute to physiology and pathophysiology.”
These probes respond to movement of ion channel voltage sensors, and it is particularly fulfilling to have conducted some of this work at the MBL, Sack says. The first measurements of voltage sensor movement were conducted at the MBL in the early 1970s by Clay M. Armstrong and Francisco Bezanilla (Nature 242: 459-461, 1973). Armstrong and Bezanilla used electrophysiological methods to measure the movement of voltage sensors. The spider toxin probe creates an optical signal when voltage sensors move, and no electrophysiology or genetic mutation of the channels is required.
Seizures and sudden death: When SUMO ‘wrestles’ potassium channels
A gene crucial for brain and heart development may also be associated with sudden unexplained death in epilepsy (SUDEP), the most common cause of early mortality in epilepsy patients.
Scientists at The University of Texas MD Anderson Cancer Center have created a new animal model for SUDEP and have shown that mice who have a partial deficiency of the gene SENP2 (Sentrin/SUMO-specific protease 2) are more likely to develop spontaneous seizures and sudden death. The finding occurred when observing mice originally bred for studying a link between SENP2 deficiency and cancer.
"SENP2 is highly present in the hippocampus, a critical brain region for seizure genesis," said Edward Yeh, M.D., chair of cardiology at MD Anderson. "Understanding the genetic basis for SUDEP is crucial given that the rate of sudden death in epilepsy patients is 20-fold that of the general population, with SUDEP the most common epilepsy-related cause of death."
Yeh’s findings were published in this month’s issue of Neuron.
Although it’s not yet known what causes SUDEP in humans, inactivation of potassium channels genes have been linked to SUDEP in animal models. Potassium channels are found in most cell types and control a large variety of cell functions.
"These animal models demonstrated an important connection between the brain and heart. However, it remains unclear whether seizure and sudden death are two separate manifestations of potassium channel deficiency in the brain and the heart, or whether seizures predispose the heart to lethal cardiac arrhythmia," said Yeh.
The study revealed that when SENP2 was deficient in the brain, seizures activated a part of the nervous system responsible for regulating the heart’s electrical system. This resulted in a phenomenon known as atrioventricular conduction block, which effectively slowed down and then stopped the heart.
Yeh’s team observed that the SENP2-deficient mice appeared normal at birth, but by 6 to 8 weeks, experienced convulsive seizures, and then sudden death. He believes the reason may lie with protein modifiers called SUMO. SENP2 deficiency results in a process known as hyper-SUMOylation, which dramatically impacts potassium channels in the brain.
"One of the channels, Kv7, is significantly diminished or ‘closed’ due to the lack of SENP2," said Yeh. "In mice this led to seizures and cardiac arrest."
In humans, the good news is that an FDA-approved drug, retigabine works by “opening” the Kv7 channel. The therapy was developed for treating partial-onset seizures. The findings in Yeh’s new mouse model clearly demonstrate a previously unknown cause of SUDEP, which may open up new opportunities for study and treatment in the future.
(Source: eurekalert.org)