科研之友
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摘要
Endogenous neurosteroids are among the most potent and efficacious potentiators of activation of GABAA receptors. It has been proposed that a conserved glutamine residue in the first membrane-spanning region (TM1 region) of the a subunits is required for binding of potentiating neurosteroids. Mutations of this residue can reduce or remove the ability of steroids to potentiate function. However, it is not known whether potentiation requires that a steroid interact with the a subunit, or not. To examine this question we mutated the homologous residue in the beta 2 and ?2L subunits to glutamine, and found that these mutations could not confer potentiation by allopregnanolone (3a5aP) when expressed in receptors containing ineffective a1 subunits. However, potentiation is restored when the entire TM1 region from the a1 subunit is transferred to the beta 2 or ?2L subunit. Mutations in the TM1 region that affect potentiation when made in the a1 subunit have similar effects when made in transferred TM1 region. Further, the effects of 3a5aP on single-channel kinetics are similar for wild-type receptors and receptors with moved TM1 regions. These results support the idea that steroids bind in the transmembrane regions of the receptor. The observations are consistent with previous work indicating that neurosteroid potentiation is mediated by an action that affects the receptor as a whole, rather than an individual subunit or pair of subunits, and in addition demonstrate that the mechanism is independent of the nature of the subunit that interacts with steroid.
- 出版日期2012-11
