Up-regulation of voltage-gated sodium channels by peptides mimicking S4-S5 linkers reveals a variation of the ligand-receptor mechanism.

Prokaryotic Na channels are tetramers and eukaryotic Na channels consist of a single subunit containing four domains. Each monomer/domain contains six transmembrane segments (S1-S6), S1-S4 being the voltage-sensor domain and S5-S6 the pore domain. A crystal structure of NaMs, a prokaryotic Na channel, suggests that the S4-S5 linker (S4-S5) interacts with the C-terminus of S6 (S6) to stabilize the gate in the open state.

C-terminal phosphorylation of Na1.5 impairs FGF13-dependent regulation of channel inactivation.

Voltage-gated Na (Na) channels are key regulators of myocardial excitability, and Ca/calmodulin-dependent protein kinase II (CaMKII)-dependent alterations in Na1.5 channel inactivation are emerging as a critical determinant of arrhythmias in heart failure. However, the global native phosphorylation pattern of Na1.

A long QT mutation substitutes cholesterol for phosphatidylinositol-4,5-bisphosphate in KCNQ1 channel regulation.

Introduction: Phosphatidylinositol-4,5-bisphosphate (PIP2) is a cofactor necessary for the activity of KCNQ1 channels. Some Long QT mutations of KCNQ1, including R243H, R539W and R555C have been shown to decrease KCNQ1 interaction with PIP2. A previous study suggested that R539W is paradoxically less sensitive to intracellular magnesium inhibition than the WT channel, despite a decreased interaction with PIP2.

Opposite Effects of the S4-S5 Linker and PIP(2) on Voltage-Gated Channel Function: KCNQ1/KCNE1 and Other Channels.

Voltage-gated potassium (Kv) channels are tetramers, each subunit presenting six transmembrane segments (S1-S6), with each S1-S4 segments forming a voltage-sensing domain (VSD) and the four S5-S6 forming both the conduction pathway and its gate. S4 segments control the opening of the intracellular activation gate in response to changes in membrane potential. Crystal structures of several voltage-gated ion channels in combination with biophysical and mutagenesis studies highlighted the critical role of the S4-S5 linker (S4S5(L)) and of the S6 C-terminal part (S6(T)) in the coupling between the VSD and the activation gate.