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Mutations of the GABA-A Receptor 1 Subunit M1 Domain Reveal Unexpected Complexity for Modulation by Neuroactive Steroids

Department of Anesthesiology (G.A., P.L., J.B., J.H.S.), Mallinckrodt Institute of Radiology (D.E.R.), and Department of Developmental Biology (D.F.C.), Washington University School of Medicine, St. Louis, Missouri

Neuroactive steroids are among the most efficacious modulators of the mammalian GABA-A receptor. Previous work has proposed that receptor potentiation is mediated by steroid interactions with a site defined by the residues 1Asn407/Tyr410 in the M4 transmembrane domain and residue 1Gln241 in the M1 domain. We examined the role of residues in the 1 subunit M1 domain in the modulation of the rat 1β22L GABA-A receptor by neuroactive steroids. The data demonstrate that the region is critical to the actions of potentiating neuroactive steroids. Receptors containing the 1Q241W or 1Q241L mutations were insensitive to (3,5)-3-hydroxypregnan-20-one (35P), albeit with different underlying mechanisms. The 1Q241S mutant was potentiated by 35P, but the kinetic mode of potentiation was altered by the mutation. It is noteworthy that the 1Q241L mutation had no effect on channel potentiation by (3,5)-3-hydroxymethyl-pregnan-20-one, but mutation of the neighboring residue, 1Ser240, prevented channel modulation. A steroid lacking an H-bonding group on C3 (5-pregnan-20-one) potentiated the wild-type receptor but not the 1Q241L mutant. The findings are consistent with a model in which the 1Ser240 and 1Gln241 residues shape the surface to which steroid molecules bind.

Address correspondence to: Gustav Akk, Department of Anesthesiology, Washington University School of Medicine, Campus Box 8054, 660 S. Euclid Ave, St. Louis MO 63110. E-mail: akk{at}morpheus.wustl.edu