Histamine Potentiates N-Methyl-d-aspartate Receptors by Interacting with an Allosteric Site Distinct from the Polyamine Binding Site

Abstract

Histamine potentiates activation of native and recombinant Nmethyl-D-aspartate receptors (NMDARs), but its mechanisms of action and physiological functions in the brain remain controversial. Using four different models, we have further investigated the histamine-induced potentiation of various NMDAR-mediated responses. In single cultured hippocampal neurons, histamine potentiated NMDA currents. It also potentiated the NMDA-induced increase in intracellular calcium in the absence, as well as with saturating concentrations, of exogenous D-serine, indicating both glycine-dependent and glycine-independent components of its effect. In rat hippocampal synaptosomes, histamine strongly potentiated NMDA-induced [ 3 H]noradrenaline release. The profile of this response contained several signatures of the histaminemediated effect at neuronal or recombinant NMDARs. It was NR2B-selective, being sensitive to micromolar concentrations of ifenprodil. It was reproduced by tele-methylhistamine, the metabolite of histamine in brain, and it was antagonized by impromidine, an antagonist/inverse agonist of histamine on NMDA currents. Up to now, histamine was generally considered to interact with the polyamine site of the NMDAR. However, spermine did not enhance NMDA-induced [ H]ifenprodil binding, whereas histamine and tele-methylhistamine had no effect. In conclusion, the histamine-induced potentiation of NMDARs occurs in the brain under normal conditions. Histamine does not bind to the polyamine site, but to a distinct entity, the so-called histamine site of the NMDAR.Histamine neurons constitute a long and highly divergent system arising from the tuberomammillary nucleus in the posterior hypothalamus and projecting in a diffuse manner to many cerebral areas. The function of these neurons in the modulation of physiological processes such as arousal or cognitive functions is well documented, but their involvement in brain disorders remains poorly understood. In the brain, the effects of histamine are mediated by three histamine receptor subtypes (H 1 , H 2 , and H 3 ), which are all G protein-coupled receptors. Brain histamine is metabolized via transmethylation into tele-methylhistamine (MeHA) catalyzed by histamine N-methyltransferase, and this metabolite is devoid of any activity at histamine receptors (Brown et al., 2001).More than 15 years ago, histamine has been reported to act as a positive allosteric modulator of the N-methyl-Daspartate receptor (NMDAR). Histamine potentiated NMDA currents in isolated (Vorobjev et al., 1993) and cultured (Bekkers, 1993) hippocampal neurons. Its effect resulted from a direct interaction with the NMDAR, the potentiation being observed on recombinant NMDARs. Moreover, it was selective for receptors containing NR1

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

“…In addition, ATP may have actions on NMDA receptors (Kloda et al, 2004). It is noteworthy that aminoglycoside antibiotics (Masuko et al, 1999b) and histamine (Bekkers, 1993;Vorobjev et al, 1993;Williams, 1994;Burban et al, 2010) have been suggested to selectively potentiate the function of GluN2B-containing NMDA receptors. By contrast, some H3-histamine receptor competitive antagonists also bind to the GluN2B ATD to inhibit receptor function, perhaps at a site overlapping the histamine binding site .…”

Differential effects of histamine H3 receptor inverse agonist thioperamide, given alone or in combination with the N-methyl-d-aspartate receptor antagonist dizocilpine, on reconsolidation and consolidation of a contextual fear memory in mice

“…For instance, histamine can amplify NMDA currents and synaptosomes glutamate release in cultured hippocampal neurons (see reviews by Brown et al, 2001;Haas et al, 2008). Importantly, histamine activation of NMDA receptors in synaptosomes has been shown to depend, at least partly, on an allosteric site located on these receptors, suggesting specific functions for the histamine-glutamate interactions (Burban et al, 2010;Hansen et al, 2010).…”

The histamine H3-receptor inverse agonist Pitolisant improves fear memory in mice

“…In addition to the mechanism proposed above to explain how Pitolisant ameliorates consolidation per se, other neural mechanisms might be involved in its actions on amnesia produced by dizocilpine. Histamine can potentiate NMDA receptors by interacting with an allosteric site located on these receptors [40]. In cultured hippocampal cells, histamine enhanced NMDA receptor-mediated transmission [41] and this histamine-NMDA interaction could mediate the ability of histamine to reverse dizocilpine-induced amnesia [42].…”