Journal
BMB REPORTS
Volume 54, Issue 6, Pages 311-316Publisher
KOREAN SOCIETY BIOCHEMISTRY & MOLECULAR BIOLOGY
DOI: 10.5483/BMBRep.2021.54.6.231
Keywords
Ethanol; Kv7.2/7.3 channel; Open probability; PI(4,5)P-2; Tetraethylammonium
Categories
Funding
- National Research Foundation of Korea (NRF) - Korea government (MSIP) [2019R1A2B5B01070546]
- Basic Science Research Program [2020R1A4A1019436]
- National Research Foundation of Korea [2019R1A2B5B01070546] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Ethanol affects neuronal activity by reducing the open probability and PI(4,5)P-2 sensitivity of Kv7.2/7.3 channels in a cell type-specific manner, leading to an increase in membrane excitability in sympathetic neurons.
Ethanol often causes critical health problems by altering the neuronal activities of the central and peripheral nerve systems. One of the cellular targets of ethanol is the plasma membrane proteins including ion channels and receptors. Recently, we reported that ethanol elevates membrane excitability in sympathetic neurons by inhibiting Kv7.2/7.3 channels in a cell type-specific manner. Even though our studies revealed that the inhibitory effects of ethanol on the Kv7.2/7.3 channel was diminished by the increase of plasma membrane phosphatidylinositol 4,5-bisphosphate (PI (4,5)P-2), the molecular mechanism of ethanol on Kv7.2/7.3 channel inhibition remains unclear. By investigating the kinetics of Kv7.2/7.3 current in high K+ solution, we found that ethanol inhibited Kv7.2/7.3 channels through a mechanism distinct from that of tetraethylammonium (TEA) which enters into the pore and blocks the gate of the channels. Using a non-stationary noise analysis (NSNA), we demonstrated that the inhibitory effect of ethanol is the result of reduction of open probability (P-O) of the Kv7.2/7.3 channel, but not of a single channel current (i) or channel number (N). Finally, ethanol selectively facilitated the kinetics of Kv7.2 current suppression by voltage-sensing phosphatase (VSP)-induced PI(4,5)P-2 depletion, while it slowed down Kv7.2 current recovery from the VSP-induced inhibition. Together our results suggest that ethanol regulates neuronal activity through the reduction of open probability and PI(4,5)P-2 sensitivity of Kv7.2/7.3 channels.
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