2.4 H3R and neural excitability
The human H3R gene is located on chromosome 20, encoding Gi/o-protein coupled receptor (326-445 amino-acids) (Arrang, Garbarg & Schwartz, 1983). The distribution of H3R has been found in cerebral cortex, nucleus accumbens, striatum, olfactory tubercles and substantia nigra, hippocampus, and hypothalamus. The H3R is located on the soma, axon, dendrites, and varicosities of histaminergic neurons, as well as the axon of non-histaminergic neurons (Stevens, Eriksson, Brown & Haas, 2001). Additionally, it has been found that H3R is located on endothelial cells. The H3R mainly located presynaptically is identified as the autoreceptor to regulate the synthesis and release of histamine in histaminergic neurons and acts as heteroreceptor to regulate other neurotransmitters in non-histaminergic neurons. H3R activation inhibits the calcium channels (Lundius, Sanchez-Alavez, Ghochani, Klaus & Tabarean, 2010), and activates the inwardly-rectifying potassium channels blocking nerve depolarization (De Luca et al., 2016), which inhibits the synthesis and release of histamine and other neurotransmitters, including glutamate, GABA, noradrenaline, dopamine, acetylcholine, and serotonin. The H3R also inhibits AA to form cAMP (Lovenberg et al., 1999), activates MAPK, Akt/glycogen synthase kinase 3β (GSK3β) and phospholipase A2 (PLA2) (Giovannini et al., 2003; Sadek, Saad, Sadeq, Jalal & Stark, 2016). Apart from presynaptic location, it has been reported H3R also present on postsynaptic location in basal ganglia colocalized with dopamine receptor 1 and 2 (Ellenbroek & Ghiabi, 2014).
H3R plays a complex role in the modulation of neural excitability, depending on the targeted neurotransmitter. Histamine inhibits spontaneous GABA release from presynaptic nerve terminals projecting to ventromedial hypothalamic neurons by inhibiting presynaptic P/Q-type Ca2+ channels via a G-protein coupled to H3R and this may modulate the excitability of ventromedial hypothalamic neurons (Jang, Rhee, Watanabe, Akaike & Akaike, 2001). H3R reduces the coupling of fast excitatory postsynaptic field potentials to population spikes of hippocampal dentate gyrus granule cells (Varaschin, Rosenberg, Hamilton & Savage, 2014), and inhibits the TMN histaminergic neurons and substantia nigra pars reticulate inhibitory neuron (De Luca et al., 2016; Zhou, Xu, Zhao, LeDoux & Zhou, 2006). It needs to be noted that histamine reduces the excitatory gain of D1-expressing medium spiny neurons in nucleus accumbens core by H3R dependent long-term depression through Gβγ-Akt/GSK3β signaling pathway (Manz, Becker, Grueter & Grueter, 2020).
Since H3R discovery, there are kinds of research focus on the drug discovery of these ligands (Szczepanska, Kuder & Kiec-Kononowicz, 2018). Agonists or antagonists target H1R/H2R/H3R or H1R/H2R/H3R knock out (KO) mice are commonly used to study the function of these receptors in the brain (Schneider, Neumann & Seifert, 2014; Toyota et al., 2002).