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Occupation of either site for the neurosteroid allopregnanolone potentiates the opening of the GABAA receptor induced from either transmitter binding site.
Bracamontes J, McCollum M, Esch C, Li P, Ann J, Steinbach JH, Akk G.
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Potentiating neuroactive steroids are potent and efficacious modulators of the GABA(A) receptor that act by allosterically enhancing channel activation elicited by GABA. Steroids interact with the membrane-spanning domains of the α subunits of the receptor, whereas GABA binds to pockets in the interfaces between β and α subunits. Steroid interaction with a single site is known to be sufficient to produce potentiation, but it is not clear whether effects within the same β-α pair mediate potentiation. Here, we have investigated whether the sites for GABA and steroids are functionally linked (i.e., whether the occupancy of a steroid site selectively affects activation elicited by GABA binding to the transmitter binding site within the same β-α pair). For that, we used receptors formed of mutated concatenated subunits to selectively eliminate one of the two GABA sites and one of the two steroid sites. The data demonstrate that receptors containing a single functional GABA site are potentiated by the neurosteroid allopregnanolone regardless of whether the steroid interacts with the α subunit from the same or the other β-α pair. We conclude that steroids potentiate the opening of the GABA(A) receptor induced by either agonist binding site.
Akaike,
Kinetic properties of the pentobarbitone-gated chloride current in frog sensory neurones.
1987, Pubmed
Akaike,
Kinetic properties of the pentobarbitone-gated chloride current in frog sensory neurones.
1987,
Pubmed Akk,
Neurosteroid access to the GABAA receptor.
2005,
Pubmed Akk,
Kinetic and structural determinants for GABA-A receptor potentiation by neuroactive steroids.
2010,
Pubmed Akk,
Mutations of the GABA-A receptor alpha1 subunit M1 domain reveal unexpected complexity for modulation by neuroactive steroids.
2008,
Pubmed Akk,
Pharmacology of structural changes at the GABA(A) receptor transmitter binding site.
2011,
Pubmed
,
Xenbase Akk,
Activation and modulation of concatemeric GABA-A receptors expressed in human embryonic kidney cells.
2009,
Pubmed Amin,
GABAA receptor needs two homologous domains of the beta-subunit for activation by GABA but not by pentobarbital.
1993,
Pubmed
,
Xenbase Baumann,
Forced subunit assembly in alpha1beta2gamma2 GABAA receptors. Insight into the absolute arrangement.
2002,
Pubmed
,
Xenbase Baumann,
Subunit arrangement of gamma-aminobutyric acid type A receptors.
2001,
Pubmed
,
Xenbase Baumann,
Individual properties of the two functional agonist sites in GABA(A) receptors.
2003,
Pubmed
,
Xenbase Baur,
Benzodiazepines affect channel opening of GABA A receptors induced by either agonist binding site.
2005,
Pubmed
,
Xenbase Bianchi,
Neurosteroids shift partial agonist activation of GABA(A) receptor channels from low- to high-efficacy gating patterns.
2003,
Pubmed Boileau,
Tandem subunits effectively constrain GABAA receptor stoichiometry and recapitulate receptor kinetics but are insensitive to GABAA receptor-associated protein.
2005,
Pubmed Bracamontes,
Steroid interaction with a single potentiating site is sufficient to modulate GABA-A receptor function.
2009,
Pubmed
,
Xenbase Curtis,
Potentiation of human alpha4beta2 neuronal nicotinic acetylcholine receptor by estradiol.
2002,
Pubmed
,
Xenbase Ho,
Site-directed mutagenesis by overlap extension using the polymerase chain reaction.
1989,
Pubmed Hosie,
Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites.
2006,
Pubmed Jin,
A portable site: a binding element for 17β-estradiol can be placed on any subunit of a nicotinic α4β2 receptor.
2011,
Pubmed
,
Xenbase Kash,
Structural elements involved in activation of the gamma-aminobutyric acid type A (GABAA) receptor.
2004,
Pubmed Li,
Neurosteroid migration to intracellular compartments reduces steroid concentration in the membrane and diminishes GABA-A receptor potentiation.
2007,
Pubmed Li,
Hydrogen bonding between the 17beta-substituent of a neurosteroid and the GABA(A) receptor is not obligatory for channel potentiation.
2009,
Pubmed McKernan,
Which GABAA-receptor subtypes really occur in the brain?
1996,
Pubmed Muroi,
Distinct structural changes in the GABAA receptor elicited by pentobarbital and GABA.
2009,
Pubmed
,
Xenbase Paradiso,
The C terminus of the human nicotinic alpha4beta2 receptor forms a binding site required for potentiation by an estrogenic steroid.
2001,
Pubmed
,
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