2023-11-20 09:38:43
Los ion channels They are cell membrane proteins that are opened by mechanical stimuli such as voltage. When this varies, a change in conformation occurs in an area of the channel called ‘voltage sensor’, which is connected, in turn, to another area called ‘pore’.
It is log acts as a pathway ion passage (potassium, sodium, calcium, etc.) from inside the cell to the outside, to the extracellular medium, or vice versa, a flow that produces a current and can be measured. The correct functioning of ion channels ensures that excitable cells such as neurons function, activate and propagate the nerve impulse.
The activation and inactivation of the potassium channel Kv2.1, present in the central nervous system, are crucial to regulate the electrical activity of neurons
Now, researchers at the National Institute of Neurological Disorders and Stroke (NINDS, one of the National Institutes of Health from the USA) have studied the potassium channel Kv2.1present in the central nervous system, where its activation and inactivation are crucial to regulate the intrinsic electrical activity of neurons.
The results are published in the journal Naturewith the Spanish Anabel Fernández Mariño as the first author.
It is also known that mutations in the gene that codes for this channel cause infantile epileptic encephalopathy, which causes seizures in some babies, boys and girls. The mechanisms by which these mutations cause the disease – of various types – are not clear, but this study may help clarify them.
3D structure of the canal
To better understand how the Kv2.1 channel or protein works, the authors have first determined its three dimensional structure through cryogenic electron microscopy. This technique, together with electrophysiological studies, have helped them understand how mutations can cause the disease.
Lateral and external view of the Kv2.1 potassium channel structure, where the green balls represent potassium ions. / A. Fernández-Mariño et al. /Nature
Thus, “by studying multiple mutations that cause epileptic encephalopathies, we discovered one, called F412L mutationwhich accelerates the inactivation of this potassium channel, making it virtually non-functioning,” says Fernández Mariño.
By studying mutations that cause epileptic encephalopathies, we have discovered that F412L accelerates the inactivation of this potassium channel, making it virtually non-functioning.
Anabel Fernández Mariño (NINDS, NIH)
“Therefore,” he continues, “it is possible that the function of the neurons that have the mutated channel is affected and this gives rise to the disease, although we need experiments in neurons and animal models to better understand the effect of the mutation.”
The hydrophobic nexus
However, the discovery of the F412L mutation has made it possible to discover a region o’hydrophobic nexus’ [que repele el agua] which controls the inactivation of the potassium channel and, surely, also others, such as sodium and calcium channels, according to the authors.
“Unexpectedly, when aligning protein structures and sequences with other sodium, potassium and calcium channelswe realized that this hydrophobic link also appears in these channels, which suggests that the inactivation mechanism through this link could act in all of them,” points out Fernández Mariño.
The hydrophobic link in the potassium channel also appears in sodium and calcium channels, suggesting that the inactivation mechanism through it could act on all of them.
If confirmed, this could explain the mutations that modify the inactivation of sodium and calcium channels, essential for the creation of the action potential of neurons and cardiovascular cells, which until now had no explanation.
Furthermore, this hydrophobic link could be relevant as a binding site for drugs that regulate ion channels. Some medications modulate their activity, stabilizing them in the inactive state. The dihydropyridines that are used to treat hypertension, for example, act through this mechanism with calcium channels, although not all the details are known.
This hydrophobic nexus could be where dihydropyridines and other drugs are binding
According to the authors, given its hydrophobic nature, this nexus could be where dihydropyridines and other drugs are binding. Future research in this field with different channels and substances that stabilize their inactivated state could help to better understand how they bind in the hydrophobic nexus and function.
“The door opens to new drug design projects and specific peptides to treat diseases related to these ion channels,” concludes the Spanish NINDS researcher.
Rights: Creative Commons.
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