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

Abstract

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 GABAA receptor channels. Previous work showed that histamine enhances the activity of recombinant GABAA 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 GABAA 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 EC10 GABA-evoked currents) with α4β3 and α4β3X isoforms, where X could be γ or δ. In contrast, histamine (1mM) had small effects on prolonging deactivation of α4β3γ2 receptors following brief (5ms) pulses of 1mM 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).

Identification of amino acids involved in histamine potentiation of GABAA receptors

“…Our study confirms the recent finding ( Saras et al, 2008 ; Bianchi et al, 2011 ) that there is a robust modulatory effect of histamine on GABA A Rs with different subunit combinations. The screening of point mutated GABA A R subunits revealed that most mutations, which encompass several amino acids conserved in β subunits, did not influence histamine potentiation.…”

“…These subunits are α1–6, β1–3, γ1–3, δ, ε, 𝜃, π, and ρ1–3. Bianchi et al (2011) showed α subunit preference of histamine under low GABA concentrations.…”

“…Since 2008, it has been known that histamine could directly activate homomeric GABA A Rs composed of β subunits and modulate the heteromeric GABA A Rs α1β2 and α1β2γ2 ( Saras et al, 2008 ). The modulatory effects of histamine on heteromeric GABA A Rs depend on the subunit composition of the receptors ( Bianchi et al, 2011 ). Today, 19 subunits are known ( Simon et al, 2004 ).…”

“…In the brain histamine is released from the tuberomammillary nucleus which is involved in the wake-sleep regulation. Metabotropic histamine receptors (H 1 –H 4 ) mediate the physiological functions of histamine but at least three different types of neuronal ligand-gated ion channels are modulated by histamine ( Bekkers, 1993 ; Saras et al, 2008 ; Bianchi et al, 2011 ; Kletke et al, 2013 ). The possible mechanism of the modulation of GABA A Rs in the brain is still speculative ( Saras et al, 2008 ; Bianchi et al, 2011 ).…”

Modulation of GABAA receptors by neurosteroids. A new concept to improve cognitive and motor alterations in hepatic encephalopathy

“…Pregnanolone, one of the main neurosteroids produced in the brain of hyperamonemic rats (Cauli et al 2009) inhibits α4-containing receptors in contrast to its stimulatory effect at other GABAA receptors (Adkins et al, 2001). GABAA receptors containing the α4-subunit behave pharmacologically different than GABAA receptors containing α1-, α2-, α3 subunits, for example at the benzodiazepine-site (Olsen and Sieghart, 2009;Adkins et al, 2001), for sensitivity to ethanol (Hanchar et al, 2006) or to taurine or histamine (Bianchi et al, 2011).…”