Posts tagged potassium channels
Articles and news from the latest research reports.
Researchers Gain Insight into How Ion Channels Control Heart and Brain Electrical Activity
Virginia Commonwealth University researchers studying a special class of potassium channels known as GIRKs, which serve important functions in heart and brain tissue, have revealed how they become activated to control cellular excitability.
The findings advance the understanding of the interaction between a family of signaling proteins called G proteins, and a special type of cell membrane ion pore called G protein-sensitive, inwardly rectifying potassium (GIRK) channels. The findings may one day help researchers develop targeted drugs to treat conditions of the heart such as atrial fibrillation.
In the study, published this week in the Online First section of Science Signaling, a publication of the American Association for the Advancement of Science (AAAS), researchers used a computational approach to predict the interactions between G proteins and a GIRK channel.
Rahul Mahajan, a M.D./Ph.D. candidate in the VCU School of Medicine’s Department of Physiology and Biophysics, undertook this problem for his dissertation work, under the mentorship of Diomedes E. Logothetis, Ph.D., chair of the Department of Physiology and Biophysics and the John D. Bower Endowed Chair in Physiology in the VCU School of Medicine. They developed a model and tested its predictions in cells, demonstrating how G proteins cause activation of GIRKs.
“Malfunctions of GIRK channels have been implicated in chronic atrial fibrillation, as well as in drug abuse and addiction,” said Logothetis, who is an internationally recognized leader in the study of ion channels and cell signaling mechanisms.
“Understanding the structural mechanism of Gβγ activation of GIRK channels could lead to rational based drug design efforts to combat chronic atrial fibrillation.”
In chronic atrial fibrillation, the GIRK channel is believed to be inappropriately open. According to Logothetis, if researchers are able to target only the specific site that keeps the channel inappropriately open, then any unrelated channels could be left unaltered, thus avoiding unwanted side effects.
Crystal structures of GIRK channels, which preceded the current study, have revealed two constrictions of the ion permeation pathway that researchers call “gates”: one at the inner leaflet of the membrane bilayer and the other close by in the cytosol, which is the liquid found inside cells.
“The structure of the Gβγ -GIRK1 complex reveals that Gβγ inserts a part of it in a cleft formed by two cytosolic loops of two adjacent channel subunits,” Logothetis said. “This is also the place where alcohols bind to activate the channel. One can think of this cleft as a clam that has its shells either open or shut closed. Stabilization of this cleft in the ‘open’ position stabilizes the cytosolic gate in the open state.”
GIRKs are activated when they interact with G proteins coupled to receptors bound to stimulatory hormones or neurotransmitters. In heart tissue, acetylcholine released by the vagus nerve activates these channels, which hyperpolarize the membrane potential and slow heart rate. In brain tissue, GIRKs inhibit excitation by acting at postsynaptic cells.
G proteins are composed of three subunits, a, b, and g. Since 1987, researchers have known that the Gbgsubunits directly activate the atrial GIRK channel, but an atomic resolution picture of how the two proteins interact remained elusive until now.
Moving forward, the team would like to use computational and experimental approaches to build and test the structures of the rest of the components of the G protein complex – for example, the Ga subunits and the G protein-coupled receptor – around the Gβγ-channel complex, which is the structure the team has already achieved.
Pitt team finds mechanism that causes noise-induced tinnitus and drug that can prevent it
An epilepsy drug shows promise in an animal model at preventing tinnitus from developing after exposure to loud noise, according to a new study by researchers at the University of Pittsburgh School of Medicine. The findings, reported this week in the early online version of the Proceedings of the National Academy of Sciences, reveal for the first time the reason the chronic and sometimes debilitating condition occurs.
An estimated 5 to 15 percent of Americans hear whistling, clicking, roaring and other phantom sounds of tinnitus, which typically is induced by exposure to very loud noise, said senior investigator Thanos Tzounopoulos, Ph.D., associate professor and member of the auditory research group in the Department of Otolaryngology, Pitt School of Medicine.
"There is no cure for it, and current therapies such as hearing aids don’t provide relief for many patients," he said. "We hope that by identifying the underlying cause, we can develop effective interventions."
The team focused on an area of the brain that is home to an important auditory center called the dorsal cochlear nucleus (DCN). From previous research in a mouse model, they knew that tinnitus is associated with hyperactivity of DCN cells — they fire impulses even when there is no actual sound to perceive. For the new experiments, they took a close look at the biophysical properties of tiny channels, called KCNQ channels, through which potassium ions travel in and out of the cell.
"We found that mice with tinnitus have hyperactive DCN cells because of a reduction in KCNQ potassium channel activity," Dr. Tzounopoulos said. "These KCNQ channels act as effective "brakes" that reduce excitability or activity of neuronal cells."
In the model, sedated mice are exposed in one ear to a 116-decibel sound, about the loudness of an ambulance siren, for 45 minutes, which was shown in previous work to lead to the development of tinnitus in 50 percent of exposed mice. Dr. Tzounopoulos and his team tested whether an FDA-approved epilepsy drug called retigabine, which specifically enhances KCNQ channel activity, could prevent the development of tinnitus. Thirty minutes into the noise exposure and twice daily for the next five days, half of the exposed group was given injections of retigabine.
Seven days after noise exposure, the team determined whether the mice had developed tinnitus by conducting startle experiments, in which a continuous, 70 dB tone is played for a period, then stopped briefly and then resumed before being interrupted with a much louder pulse. Mice with normal hearing perceive the gap in sounds and are aware something had changed, so they are less startled by the loud pulse than mice with tinnitus, which hear phantom noise that masks the moment of silence in between the background tones.
The researchers found that mice that were treated with retigabine immediately after noise exposure did not develop tinnitus. Consistent with previous studies, 50 percent of noise-exposed mice that were not treated with the drug exhibited behavioral signs of the condition.
"This is an important finding that links the biophysical properties of a potassium channel with the perception of a phantom sound," Dr. Tzounopoulos said. "Tinnitus is a channelopathy, and these KCNQ channels represent a novel target for developing drugs that block the induction of tinnitus in humans."
The KCNQ family is comprised of five different subunits, four of which are sensitive to retigabine. He and his collaborators aim to develop a drug that is specific for the two KCNQ subunits involved in tinnitus to minimize the potential for side effects.
"Such a medication could be a very helpful preventive strategy for soldiers and other people who work in situations where exposure to very loud noise is likely," Dr. Tzounopoulos said. "It might also be useful for other conditions of phantom perceptions, such as pain in a limb that has been amputated."
(Source: eurekalert.org)
Discovery of genetic defect which triggers epilepsy
Researchers at the University Department of Neurology at the MedUni Vienna have identified a gene behind an epilepsy syndrome, which could also play an important role in other idiopathic (genetically caused) epilepsies. With the so-called “next generation sequencing”, with which genetic changes can be identified within a few days, it was ascertained that the CNTN2 gene is defective in this type of epilepsy.
This was investigated by a team led by Elisabeth Stögmann in collaboration with Cairo’s Ain Shams University and the Helmholtz Centre Munich with reference to a particular Egyptian family, in which five sick children have resulted from the marriage of one healthy cousin to his, likewise healthy, second cousin. The children affected suffer from a specific epilepsy syndrome, in which different types of epileptic attacks occur. This constellation has the “advantage”, according to Stögmann, that both alleles of the gene, which is how one designates different forms of the gene, demonstrate this defect: “As a result the defect becomes symptomatic and identifiable.
"20,000 to 25,000 genes, including all the "protein coding" ones, were sequenced for this. When this was done a mutation was found in the CNTN2 gene. CNTN2 undertakes an important function in the anchoring of potassium channels to the synapses. The mutation makes it no longer possible to generate this protein and, as a consequence, the potassium channels no longer remain affixed to the synapses. The researchers suspect that the epilepsy in this family is triggered by the altered function of the potassium channels.
This discovery, which has now been published in the top journal “Brain”, is providing the stimulus for further research to investigate this particular gene in other epilepsy patients as well. Approximately one percent of the population suffers from active epilepsy in which regular epileptic fits occur. The danger of suffering from an epileptic fit once in your life lies at approximately four to five percent. Genetic factors play a major part in the occurrence of epilepsies.
(Source: meduniwien.ac.at)