Activation of alpha 6-containing GABA(A) receptors by pentobarbital occurs through a different mechanism than activation by GABA

作者：Fisher Matthew T; Fisher Janet L^*

来源：Neuroscience Letters, 2010, 471(3): 195-199.

DOI：10.1016/j.neulet.2010.01.041

• GABA
• Barbiturates
• Mutation
• Patch clamp

The GABA(A) receptors are ligand-gated chloride channels which are the targets for many clinically used sedatives, including the barbiturates. The barbiturate pentobarbital acts through multiple sites on the GABA(A) receptor. At low concentrations (mu M), it acts as a positive allosteric modulator while at higher concentrations it can directly activate the receptor. This agonist action is influenced by the subunit composition of the receptor, and pentobarbital is a more effective agonist than GABA only at receptors containing an alpha 6 subunit. The conformational change that translates GABA binding into channel opening is known to involve a lysine residue located in an extracellular domain between the 2nd and 3rd transmembrane domains. Mutations of this residue disrupt activation of the channel by GABA and have been linked to inherited epilepsy. Pentobarbital binds to the receptor at a different agonist site than GABA, but could use a common signal transduction mechanism to gate the channel. To address this question. we compared the effect of a Mutating the homologous lysine residue in the alpha 1 or alpha 6 subunits (K278 or K277, respectively) to methionine on direct activation of recombinant GABA(A) receptors by GABA or pentobarbital. We found that this mutation reduced GABA sensitivity for both alpha 1 and alpha 6 subunits, but affected pentobarbital sensitivity only for the alpha 1 subunit. This suggests that pentobarbital acts through a distinct signal transduction pathway at the alpha 6 subunit, which may account for its greater efficacy compared to GABA at receptors containing this subunit.

• 出版日期2010-3-8