Abstract
Voltage‐dependent inactivation of ion channels contributes to the regulation of the membrane potential of excitable cells. Mouse polycystic kidney disease 2‐like 1 (PKD2L1) forms voltage‐dependent nonselective cation channels, which are activated but subsequently inactivated in response to membrane depolarization. Here, we found that the mutation of an asparagine 533 residue (N533Q) in the outer pore loop region of PKD2L1 caused a marked increase in outward currents induced by depolarization. In addition, the tail current analysis demonstrated that the N533Q mutants are activated during depolarization but the subsequent inactivation does not occur. Interestingly, the N533Q mutants lacked the channel activation triggered by the removal of stimuli such as extracellular alkalization and heating. Our findings suggest that the N533 residue in the outer pore loop region of PKD2L1 has a key role in the voltage‐dependent channel inactivation.
Highlights
Voltage-dependent inactivation of ion channels contributes to the regulation of the membrane potential of excitable cells
Depolarization-triggered outward currents of the polycystic kidney disease 2-like 1 (PKD2L1) channels are small, large tail currents are observed during the subsequent repolarization, suggesting that PKD2L1 channels activate but immediately inactivate upon depolarization
HEK293T cells overexpressing the WT channels showed typical PKD2L1 currents; that is, the outward currents triggered by depolarization were small, but larger tail currents were observed upon repolarization to À100 mV (Fig. 2A–C)
Summary
Voltage-dependent inactivation of ion channels contributes to the regulation of the membrane potential of excitable cells. Mouse polycystic kidney disease 2-like 1 (PKD2L1) forms voltage-dependent nonselective cation channels, which are activated but subsequently inactivated in response to membrane depolarization. Our findings suggest that the N533 residue in the outer pore loop region of PKD2L1 has a key role in the voltage-dependent channel inactivation. The tail currents triggered by the following repolarization represent quick transition of the PKD2L1 channel from inactivated to open states. The voltage-dependent inactivation is essential for robust activation of the PKD2L1 channels upon repolarization. As the voltage-dependent gating of the PKD2L1 channel has some resemblance to that of the HERG K+ channel, in the present study, we focused on amino acid residues behind the selectivity filter of the PKD2L1 channel, N531 and N533, to investigate the mechanism of the PKD2L1 channel inactivation
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