Mutagenesis and computational docking studies support the existence of a histamine binding site at the extracellular β3+β3- interface of homooligomeric β3 GABAA receptors.

Histamine is an important neurotransmitter that exerts its physiological actions through H1-4 metabotropic receptors in mammals. It also directly activates ionotropic GABAA receptor (GABAAR) β3 homooligomers and potentiates GABA responses in αβ heterooligomers in vitro, but the respective histamine binding sites in GABAARs are unknown. We hypothesized that histamine binds at the extracellular β+β- interface at a position homologous to the GABA binding site of heterooligomeric GABAARs.

Histamine-gated ion channels in mammals?

There is ample pharmacological and physiological evidence for yet unidentified histamine receptors in mammalian brain that are linked to a Cl(-) conductance. In invertebrates, two histamine-gated chloride channels (HisCl α1 and α2) are already well known. HisCl channels are members of the Cys-loop receptor superfamily of ligand-gated ion channels and are closely related to the mammalian GABA(A) and glycine receptors (GlyR).