Assessment of molecular action of direct gating and allosteric modulatory effects of carisoprodol (SomaRTM) on GABA A receptors

Abstract

Meprobamate (tradenames Miltown, Equanil) is a schedule IV anxiolytic and the primary metabolite of the muscle relaxant carisoprodol. Meprobamate modulates GABAA (aminobutyric acid type A) receptors, and has been described as having barbiturate-like activity. A thorough understanding of its mechanism remains ill-defined, however. To gain insight into its actions, we have conducted a series of studies using recombinant GABAA receptors. In xz GABAA receptors (where x = 1-6 and z = 1-3), the ability to enhance GABA-mediated current was evident for all  subunit isoforms, with the largest effect observed in 5-expressing receptors. Direct gating was comparable with all  subunits, although the effect was attenuated in α3-expressing receptors. Allosteric potentiating and direct gating effects were comparable in 112 and 122 receptors, whereas allosteric effects were enhanced in 12 compared to 122 receptors. In "extrasynaptic" GABAA receptors (α1β3δ and α4β3δ receptors), meprobamate allosterically enhanced both EC20 and saturating GABA currents, and directly activated these receptors with an efficacy comparable to that of GABA. Bemegride, which antagonizes effects of pentobarbital, attenuated direct gating effects of meprobamate. Whereas pentobarbital directly gated homomeric β3 receptors, meprobamate did not, and instead blocked the spontaneously open current present in these receptors. In wild type homomeric ρ1 DEDICATION I dedicate my dissertation to my mother Mrs. Manju Kumari whose tireless patience and encouragement helped me in toughest of the times. My Grand Father, Late Mr. Awadh Kishore Das. My aunt Bindu Kumari, whose first words when I joined medical school was, "win a Nobel prize in medicine". My father, Mr. Sachchidanand Roy, who stood behind me through thick and thin and last but not the least, my mentor Dr. Glenn H. Dillon. v ACKNOWLEDGMENTS I would like to thank these important people who have helped and guided me in achieving my goals. Dr. Glenn H. Dillon: An excellent mentor, excellent scientist, excellent administrator, excellent family man and an amazing person. I am extremely lucky to have you as mentor for not only learning science but every moment spent with you was a learning experience. So, Thank you. Dawn Dillon: An amazing person, who did not let us miss our family away from home. Thank you.