The wake-promoting transmitter histamine preferentially enhances α-4 subunit-containing GABAA receptors

Histamine is an important wake-promoting neurotransmitter that activates seven-transmembrane G-protein coupled histamine receptors. However, histamine demonstrates target promiscuity, including direct interaction with the structurally unrelated glutamate (NMDA) and GABA(A) receptor channels. Previous work showed that histamine enhances the activity of recombinant GABA(A) receptor isoforms typically found in synaptic locations, although co-release of histamine and GABA is not known to occur in vivo. Here we used patch clamp recordings of various recombinant GABA(A) receptor isoforms (α1-6, β1-3, γ1-3, δ) to test the hypothesis that histamine might show subunit preference under low GABA concentration (extrasynaptic) conditions. We found that histamine potentiated the whole-cell responses to GABA for all tested subunit combinations. However, the magnitude of enhancement was largest (∼400% of EC(10) GABA-evoked currents) with α4β3 and α4β3X isoforms, where X could be γ or δ. In contrast, histamine (1 mM) had small effects on prolonging deactivation of α4β3γ2 receptors following brief (5 ms) pulses of 1 mM GABA. These findings suggest GABA-histamine cross-talk may occur preferentially at low GABA concentrations, which could theoretically be inhibitory (via enhancing tonic inhibition), directly excitatory (via enhancing presynaptic GABAergic signaling), or indirectly excitatory (via inhibiting GABAergic interneurons).