Key result
The R230C mutation in KCNQ3 shifts the open/closed transition of the gate to very negative potentials, resulting in the mutated channel remaining open throughout the physiological voltage range.
Why the study?
Malfunction of potassium channels formed by KCNQ2 and KCNQ3 causes neuronal hyperexcitability, but the molecular mechanisms by which epilepsy-associated mutations in the KCNQ3 voltage sensor cause channel malfunction remained unclear.
The R230C mutation in KCNQ3 causes channel malfunction by shifting the open/closed transition to very negative potentials, suggesting that compounds shifting S4 activation to more positive potentials could have therapeutic potential for epilepsy.
Answers are grounded in this paper and cite their sources.
Provides mechanistic insight into KCNQ3 epilepsy mutations; leaves open clinical translation pending further validation.
One of the major factors known to cause neuronal hyperexcitability is malfunction of the potassium channels formed by KCNQ2 and KCNQ3. These channel subunits underlie the M current, which regulates neuronal excitability. Here, I investigate the molecular mechanisms by which epilepsy-associated mutations in the voltage sensor (S4) of KCNQ3 cause channel malfunction. Voltage clamp fluorometry reveals that the R230C mutation in KCNQ3 allows S4 movement but shifts the open/closed transition of the gate to very negative potentials. This results in the mutated channel remaining open throughout the physiological voltage range. Substitution of R230 with natural and unnatural amino acids indicates that the functional effect of the arginine residue at position 230 depends on both its positive charge and the size of its side chain. I find that KCNQ3-R230C is hard to close, but it is capable of being closed at strong negative voltages. I suggest that compounds that shift the voltage dependence of S4 activation to more positive potentials would promote gate closure and thus have therapeutic potential.
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René Barro-Soria (2018) studied Epilepsy. R230C mutation in KCNQ3 was evaluated on Voltage dependence of channel opening. The R230C mutation in KCNQ3 shifts the open/closed transition of the gate to very negative potentials, resulting in the mutated channel remaining open throughout the physiological voltage range.
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