A Cation-π Binding Interaction with a Tyrosine in the Binding Site of the GABA_C Receptor

Abstract

GABA_C (ρ) receptors are members of the Cys-loop superfamily of neurotransmitter receptors, which includes nicotinic acetylcholine (nACh), 5-HT₃, and glycine receptors. As in other members of this family, the agonist binding site of GABA_C receptors is rich in aromatic amino acids, but while other receptors bind agonist through a cation-π interaction to a tryptophan, the GABA_C binding site has tyrosine at the aligning positions. Incorporating a series of tyrosine derivatives at position 198 using unnatural amino acid mutagenesis reveals a clear correlation between the cation-π binding ability of the side chain and EC₅₀ for receptor activation, thus demonstrating a cation-π interaction between a tyrosine side chain and a neurotransmitter. Comparisons among four homologous receptors show variations in cation-π binding energies that reflect the nature of the cationic center of the agonist.

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