Modification of hERG1 channel gating by Cd2+

Area of Science:

• Molecular Biology
• Biophysics
• Ion Channel Physiology

Background:

• Voltage-gated potassium channels (hERG1) possess voltage sensor domains (VSDs) with S1-S4 segments.
• S4 segment displacement during voltage changes generates gating currents via interactions with S2 and S3 acidic residues.
• Transition metal cations can modulate channel gating by interacting with these acidic residues.

Purpose of the Study:

• To characterize the effects of cadmium ions (Cd2+) on hERG1 gating currents.
• To investigate the mechanism of Cd2+ interaction with hERG1 channel gating.
• To develop new models describing hERG1 channel gating currents.

Main Methods:

• Cut-open Vaseline gap technique in Xenopus oocytes.
• Electrophysiological recordings of hERG1 gating currents.
• Development of Markov models for channel gating.

Main Results:

• Cd2+ shifted the voltage dependence of OFF gating charge-voltage (QOFF-V) relationship by +50 mV at 0.3 mM.
• Cd2+ induced a novel, concentration- and voltage-dependent outward current (ICd-out) upon repolarization.
• Other cations (Co2+, Zn2+, La3+) did not induce a similar outward current, indicating specific Cd2+ interaction.

Conclusions:

• Cd2+ competes with S4 basic residues for binding to acidic residues in S2 and S3 segments of hERG1 channels.
• The outward movement of S4 during repolarization displaces bound Cd2+, generating the observed outward current.
• New Markov models accurately describe hERG1 gating currents and the effects of extracellular Cd2+.