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Mol Pharmacol
2013 Jan 01;831:235-44. doi: 10.1124/mol.112.081240.
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Distinct sensitivity of slo1 channel proteins to ethanol.
Liu J
,
Bukiya AN
,
Kuntamallappanavar G
,
Singh AK
,
Dopico AM
.
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Ethanol levels reached in circulation during moderate-to-heavy alcohol intoxication (50-100 mM) modify Ca(2+)- and voltage-gated K(+) (BK) channel steady-state activity, eventually altering both physiology and behavior. Ethanol action on BK steady-state activity solely requires the channel-forming subunit slo1 within a bare lipid environment. To identify the protein regions that confer ethanol sensitivity to slo1, we tested the ethanol sensitivity of heterologously expressed slo1 and structurally related channels. Ethanol (50 mM) increased the steady-state activities of mslo1 and Ca(2+)-gated MthK, the latter after channel reconstitution into phospholipid bilayers. In contrast, 50-100 mM ethanol failed to alter the steady-state activities of Na(+)/Cl(-)-gated rslo2, H(+)-gated mslo3, and an mslo1/3 chimera engineered by joining the mslo1 region encompassing the N terminus to S6 with the mslo3 cytosolic tail domain (CTD). Collectively, data indicate that the slo family canonical design, which combines a transmembrane 6 (TM6) voltage-gated K(+) channel (K(V)) core with CTDs that empower the channel with ion-sensing, does not necessarily render ethanol sensitivity. In addition, the region encompassing the N terminus to the S0-S1 cytosolic loop (missing in MthK) is not necessary for ethanol action. Moreover, incorporation of both this region and an ion-sensing CTD to TM6 K(V) cores (a design common to mslo1, mslo3, and the mslo1/mslo3 chimera) is not sufficient for ethanol sensitivity. Rather, a CTD containing Ca(2+)-sensing regulator of conductance for K(+) domains seems to be critical to bestow K(V) structures, whether of TM2 (MthK) or TM6 (slo1), with sensitivity to intoxicating ethanol levels.
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