A conserved threonine in the S1-S2 loop of K(V)7.2 and K(V)7.3 channels regulates voltage-dependent activation

作者：Fuell Yvonne; Seebohm Guiscard; Lerche Holger; Maljevic Snezana^*

来源：Pflugers Archiv-European Journal of Physiology, 2013, 465(6): 797-804.

DOI：10.1007/s00424-012-1184-x

• KCNQ2
• Voltage gating
• Homology model

The voltage-gated potassium channels K(V)7.2 and K(V)7.3 (KCNQ2/3 genes) play an important role in regulating neuronal excitability. More than 50 KCNQ2/3 mutations have been identified to cause an inherited form of epilepsy in newborns. For two of those (E119G and S122L) found in the S1-S2 region of K(V)7.2, we previously showed a decreased channel availability mainly at action potential subthreshold voltages caused by a slight depolarizing shift of the activation curve. Interestingly, recent studies revealed that a threonine residue within the S1-S2 loop, highly conserved among different classes of K-V channels, is crucial for both their function and surface expression. To investigate the functional role of the homologous threonine residues in K(V)7.2 (T114) and K(V)7.3 (T144) channels, we replaced them with alanine and examined the electrophysiological properties using heterologous expression in CHO cells and whole cell patch clamping. Channels comprising mutant subunits yielded decreased potassium currents with slowed activation and accelerated deactivation kinetics. However, the most striking effect was a depolarizing shift in the voltage dependence of activation reaching +30 mV upon co-expression of both mutant subunits. Potential interactions of T114 within the channel were analyzed by creating a 3D homology model of K(V)7.2 in an open state suggesting that this residue plays a central role in the formation of a stable interface between the S1-S2 and the S5 segment helices. This could be the explanation why substitution of the conserved threonine in K(V)7.2 and K(V)7.3 channels destabilizes the open and favors the closed state of these channels.

• 出版日期2013-6