Every living cell has a small, highly specialized conduit called a K + channel that transports K + to and fro. The Kv channels are sensitive to voltage changes within the cell's membranes and can choose between K and Na.
The C-type inactivation process that the selectivity filter uses allows it to act as an additional gate that can stop the flow of ionized water. When depolarization of the cell is triggered by opening the activated gate, there is a change in the selectivity filter.
The study was led by Luis Cuello, PhD, from the Texas Tech University Health Sciences Center (TTUHSC) School of Medicine.
The Cuello-Labro team included D. Marien Cortes and Laura Coonen. Their study was published in Science Advances in September of this year.
Every living cell has a unique transport mechanism that defines its function. The K + transport mechanism effectively controls a number of very complex processes such as the normal electrical activity of brain neurons, the human body's immune response against life threatening pathogens and the rhythmical beating of the human heart.
The hERG channel within the human heart needs to undergo C-type inactivation before it can function as needed to maintain the heart's periodicity. Cuello said that the cells have a resting state and must be activated to work. For the normal functioning of the human heart, it is important that they undergo C- type inactivation.
Cuello said that the channel has to be inactivated after it does start. That is important for the human heart because it needs to keep its periodicity, and the heart beating is based on that feature.
Scientists have been studying a specific Kv channel that is derived from a fruit fly for a long time. The Shaker channel is similar to the human body in that it has a role in the proper functioning of the cell.
The Shaker channel was discovered in the U.S. about 50 years ago and has been widely available ever since. It was accepted that the C-type inactivated state of a potassium channel was represented by the W434F Mutation. Cuello's team showed that is not the case.
Cuello said that the normal channel that inactivates has a structure that is different from that of the Mutant. Thanks to our work, we said, "Hey, be cautious because that Mutant channel is a very different structure, or you might have a different structure which doesn't have anything to do with the real channel in the human body." If you want to design a drug based on the assumption that the normal channel looks the same in the inactive state, that's not true.
The channel that doesn't pass ion is called the Mutant Channel. Cuello said that there were some experiments that suggested that the Mutant doesn't conduct ion channels because they are inactivated. The results of his team's experiments show that the channel is trapped in a deep inactivated state. The Shaker channel has been considered a structural surrogate to study all the channels because they are very similar to the humans.
Cuello said that the W434F is not a good comparison to the C-type in humanactivated channel that we have in the body.
Cuello said that his team's work proved that the channel doesn't lack the ability to discriminate between the two minerals.
The only thing that it doesn't do is conduct potassium. If you want to design a new drug, you need to know which part of theProtein you must tap to tackle it. We are calling attention to our work because we don't want to create a structural parallel between the inactivated channel and the normal channel in the human body. There is no structural equivalent.
Cuello's lab is moving away from studying the fruit fly K + channel and is starting to work with three different types of human K + channels. The immune system and the brain express two of the channels they are working with.
Cuello wants to study what happens when the channels are inactivated. How are we able to design drugs to tackle a particular state of the channel? We don't know if we need to target the channel when it is closed or open. If we want to design drugs for specific diseases, we need to study the human isoform of all the channels.
More information: Laura Coonen et al, The nonconducting W434F mutant adopts upon membrane depolarization an inactivated-like state that differs from wild-type Shaker-IR potassium channels, Science Advances (2022). DOI: 10.1126/sciadv.abn1731 Journal information: Science Advances
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