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).