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Zinc activates TREK-2 potassium channel activity
Jin-Sung Kim1, Jin-Yong Park, Ho-Won Kang
1Department of Life Science, Sogang University, Mapo-Gu, Sinsu-Dong 1, Seoul 121-742, Korea.
The Journal of Pharmacology and Experimental Therapeutics
|April 29, 2005
Summary
Divalent metal ions affect TWIK-related K(+) channel (TREK)-2 activity. Lead (Pb2+) inhibits TREK-2, while zinc (Zn2+) enhances it, offering a potential method for TREK-2 identification.
Area of Science:
- Neuroscience
- Molecular Biology
- Biophysics
Background:
- TWIK-related K(+) channel (TREK)-2 plays a role in neuronal excitability by influencing resting membrane potential and action potential properties.
- Understanding the modulation of TREK-2 by external factors like metal ions is crucial for comprehending its physiological functions.
Purpose of the Study:
- To investigate the effects of various divalent metal ions (Ba2+, Co2+, Ni2+, Pb2+, Zn2+) on TREK-2 channel activity.
- To identify the structural determinants responsible for zinc-mediated potentiation of TREK-2.
Main Methods:
- Functional expression of TREK-2 in Xenopus oocytes.
- Two-electrode voltage clamp electrophysiology to measure TREK-2 currents.
- Site-directed mutagenesis and chimera construction to map functional domains.
Main Results:
- Lead (Pb2+) inhibited TREK-2 currents with an IC50 of 15.6 microM.
- Zinc (Zn2+) enhanced TREK-2 activity in a dose-dependent manner (EC50 = 87.1 microM).
- Structural analysis localized the zinc-binding site to the first pore region and extracellular loop of TREK-2, involving residues like His121, His156, Asp158, and Asn177.
Conclusions:
- Divalent cations differentially modulate TREK-2 channel function, with Pb2+ acting as an inhibitor and Zn2+ as an enhancer.
- The N-terminal pore region and extracellular loop of TREK-2 are critical for zinc potentiation.
- Zn2+-induced stimulation serves as a distinguishing characteristic for TREK-2 among two-pore potassium channels.