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, 133 (5), 651-8

Straight-chain Alcohols Exhibit a Cutoff in Potency for the Inhibition of Recombinant Glutamate Receptor Subunits

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Straight-chain Alcohols Exhibit a Cutoff in Potency for the Inhibition of Recombinant Glutamate Receptor Subunits

B E Akinshola. Br J Pharmacol.

Abstract

The effects of n-alcohols (methanol to 1-decanol) on kainate-activated AMPA receptor subunit GluR1 and GluR3 ion currents were studied in Xenopus oocytes using the two-electrode voltage-clamp recording technique. For short-chain alcohols from methanol to 1-hexanol, potency for inhibition of GluR1 and GluR3 receptor-mediated current increased in proportion to the chain length or hydrophobicity of the alcohol. The IC(50) values of these alcohols for GluR1 were: methanol, 702 mM; ethanol, 170 mM; 1-propanol, 69 mM; 1-butanol, 20 mM; 1-pentanol, 17 mM; and 1-hexanol, 10 mM. For GluR3, IC(50) values were: methanol, 712 mM; ethanol, 238 mM; 1-propanol, 50 mM; 1-butanol, 32 mM; 1-pentanol, 13 mM; and 1-hexanol, 7 mM. For long-chain alcohols, 1-heptanol was less potent than 1-hexanol (estimated IC(50): 19 mM for GluR1 and 18 mM for GluR3), 1-octanol had little effect only on GluR3, and 1-nonanol and 1-decanol did not significantly inhibit both GluR1 and GluR3 responses. The observations indicate that straight-chain n-alcohols exhibit a cutoff in their potency for inhibition of the function of non-NMDA glutamate receptor subunits, GluR1 and GluR3. The cutoff in potency of n-alcohols for inhibition of non-NMDA glutamate receptor function is consistent with the interpretation that alcohols affect the function of these receptor-channels by interacting with an alcohol binding site of specific dimensions on the receptor protein.

Figures

Figure 1
Figure 1
Inhibition of kainate-activated ion-currents in oocytes expressing recombinant AMPA GluR1 receptor subunit by aliphatic n-alcohols. (a) Record of currents activated by 200 μM KA in oocytes voltage-clamped at −70 mV and the inhibition of these currents by 100 mM ethanol and 10 mM 1-hexanol. 1 mM 1-decanol did not inhibit receptor current. Current and time calibration applies to all records. (b) Concentration-response curves for inhibition of kainate-activated current by aliphatic n-alcohols from methanol to 1-decanol in oocytes expressing recombinant AMPA GluR1 receptor subunit. Values are mean (±s.e.mean) percentage inhibition of 5–8 oocytes; error bars not visible are smaller than the symbol size. Each curve was plotted by fitting the values to the logistic equation in the methods section, except for the 1-octanol, 1-nonanol and 1-decanol curves, which were fitted by linear regression.
Figure 2
Figure 2
Inhibition of kainate-activated ion-currents in oocytes expressing recombinant AMPA GluR3 receptor subunit by aliphatic n-alcohols. (a) Record of currents activated by 200 μM KA in oocytes voltage-clamped at −70 mV and the inhibition of these currents by 100 mM ethanol and 10 mM 1-hexanol. One mM 1-decanol did not inhibit receptor current. Current and time calibration applies to all records. (b) Concentration-response curves for inhibition of kainate-activated current by aliphatic n-alcohols from methanol to 1-decanol in oocytes expressing recombinant AMPA GluR3 receptor subunit. Values are mean (±s.e.mean) percentage inhibition of 5–8 oocytes; error bars not visible are smaller than the symbol size. Each curve was plotted by fitting the values to the logistic equation in the Methods section, except for the 1-octanol, 1-nonanol and 1-decanol curves.
Figure 3
Figure 3
Cutoff in the potency of aliphatic n-alcohols for inhibition of GluR1 (a) and GluR3 (b) receptor subunits. Relative potency of aliphatic n-alcohols for inhibiting receptor-mediated current in oocytes (ethanol IC50/alcohol IC50), expressed as a function of their membrane : buffer partition coefficients. Dashed line represents membrane disordering potency data for aliphatic n-alcohols from ethanol to 1-octanol, (Lyon et al., 1981). The symbols for 1-octanol, 1-nonanol, and 1-decanol are shown on the x-axis because IC50 values for these alcohols could not be determined.

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