THE SENSITIVITY OF AMPA-SELECTIVE GLUTAMATE-RECEPTOR CHANNELS TO PENTOBARBITAL IS DETERMINED BY A SINGLE AMINO-ACID RESIDUE OF THE ALPHA(2)SUBUNIT

Clinical concentrations of pentobarbital inhibit the alpha-amino-3-hyd roxy-5-methyl-4-isoxazole propionic acid (AMPA)-selective glutamate re ceptor (GluR) channels. Recently, the AMPA-selective GluR channels tha t contained the alpha 2 subunit were shown to be more sensitive to pen tobarbital block than those without the alpha 2 subunit. Here we demon strated that replacement by glutamine of the arginine residue in putat ive transmembrane segment M2 of the alpha 2 subunit (mutation alpha 2- R586Q) drastically reduced the pentobarbital sensitivity of the alpha 2 heteromeric channel to the level comparable to those of the alpha 1 and alpha 2-R586Q homomeric channels. These results suggest that the a rginine residue in segment M2 of the alpha 2 subunit is the critical d eterminant of the sensitivities of the AMPA-selective GluR channels to pentobarbital.