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). Indeed, they share particularly strong homology within the ligand binding and ion channel domains. Here we discuss the possibility that mammalian HisCl channels might exist among the known GABA(A) or GlyR subunits. Studies published to date support this hypothesis, including evidence for direct histamine gating of GABA(A) β homomers, histamine potentiation of GABA(A) αβ and αβγ heteromeric receptors, and GABA(A) receptor blockade by some antihistamines. We explore what is known about the binding-site structure, function and pharmacology of invertebrate HisCl channels and other histamine binding sites to support and inform a broader search for HisCl channels among the mammalian GABA(A) and GlyR subunits. The discovery and identification of HisCl-like channels in mammals would not only enhance understanding of inhibitory signaling and histamine function in the mammalian brain, but also provide new avenues for development of therapeutic compounds targeting this novel histamine site. This commentary is therefore intended to foster consideration of a novel and potentially important target of histamine and histaminergic drugs in the CNS.
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