The asparagine 533 residue in the outer pore loop region of the mouse PKD2L1 channel is essential for its voltage‐dependent inactivation

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 ( PKD 2L1) 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 PKD 2L1 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 PKD 2L1 has a key role in the voltage‐dependent channel inactivation.

Polycystic kidney disease 2-like 1 channel contributes to the bitter aftertaste perception of quinine

“…Quinine is a cinchona alkaloid exhibiting an antimalarial activity, which has been used as a standard bitter tastant in taste perception research 20 . In the present study, we investigated whether a bitterant, quinine, affects the constitutive PKD2L1 currents recorded in whole-cell patch-clamp recordings [17][18][19] . As shown in Fig.…”

“…The PKD2L1 channel exhibits voltage-dependent or Ca 2+ -dependent inactivation. In our previous study, the outer pore loop region of the PKD2L1 channel is demonstrated to be essential for its voltage-dependent inactivation 19 . On the other hand, the Ca 2+ -dependent inactivation is reported to be due to Ca 2+ -binding in the selectivity filter of the PKD2L1 channel 23 .…”

“…Besides, PKD2L1-deficient mice retain the sour response 16 . Therefore, the physiological roles of PKD2L1 in taste perception remain unknown.We previously demonstrated that the PKD2L1 channel is sensitive to alkalization and heating in the human embryonic kidney (HEK) 293 T cells exogenously expressing PKD2L1 [17][18][19] . Interestingly, the channel was activated after the removal of the alkaline stimuli, while the alkalization itself inactivated the channel.Here, we found that the PKD2L1 channel is involved in sensing bitterness.…”

“…We previously demonstrated that the PKD2L1 channel is sensitive to alkalization and heating in the human embryonic kidney (HEK) 293 T cells exogenously expressing PKD2L1 [17][18][19] . Interestingly, the channel was activated after the removal of the alkaline stimuli, while the alkalization itself inactivated the channel.…”

Involvement of pore helix in voltage-dependent inactivation of TRPM5 channel

“…In TRPA1 channels, L906 in the pore helix is considered to be essential for voltage-dependent gating [ 13 ]. In case of TRPP3 (also named PKD2L1), N533 in the pore loop region is essential for its voltage-dependent inactivation [ 24 ]. Thus, conformational dynamics of the pore region during voltage-dependent inactivation could be conserved among TRP channels.…”