Journal
MOLECULAR PHARMACOLOGY
Volume 74, Issue 3, Pages 614-627Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.108.048520
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Funding
- NIAAA NIH HHS [R21 AA014707-02, AA14707, R21 AA014707] Funding Source: Medline
- NIGMS NIH HHS [P01 GM047969-16, P01 GM047969, GM47969] Funding Source: Medline
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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 alpha 1Asn407/Tyr410 in the M4 transmembrane domain and residue alpha 1Gln241 in the M1 domain. We examined the role of residues in the M1 subunit M1 domain in the modulation of the rat alpha 1 beta 2 gamma 2L GABA-A receptor by neuroactive steroids. The data demonstrate that the region is critical to the actions of potentiating neuroactive steroids. Receptors containing the alpha 1Q241W or alpha 1Q241L mutations were insensitive to (3 alpha,5 alpha)-3-hydroxypregnan-20-one (3 alpha 5 alpha P), albeit with different underlying mechanisms. The alpha 1Q241S mutant was potentiated by 3 alpha 5 alpha P, but the kinetic mode of potentiation was altered by the mutation. It is noteworthy that the alpha 1Q241L mutation had no effect on channel potentiation by (3 alpha,5 alpha)-3-hydroxymethylpregnan-20-one, but mutation of the neighboring residue, alpha 1Ser240, prevented channel modulation. A steroid lacking an H-bonding group on C3 (5 alpha-pregnan-20-one) potentiated the wild-type receptor but not the alpha 1Q241L mutant. The findings are consistent with a model in which the alpha 1Ser240 and alpha 1Gln241 residues shape the surface to which steroid molecules bind.
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