2.3 H2R and neural excitability
The human H2R gene is located on chromosome 5, encoding 7-transmembrane
G-protein coupled receptor (359 amino-acids) (Traiffort, Vizuete,
Tardivel-Lacombe, Souil, Schwartz & Ruat, 1995). The H2R is coupled to
Gs G-protein, which in turn activates adenylyl cyclase to form a second
messenger cAMP. Then cAMP activates phosphokinase A (PKA), which in turn
phosphorylates downstream targets, such as cAMP response element-binding
(CREB) protein. Similar to H1R, the distribution of H2R in the brain is
wide, including cortex, basal ganglia, hippocampus, amygdala, thalamus,
and hypothalamus. The H1R and H2R are colocalized in hippocampus, locus
coeruleus, raphe nuclei, substantia nigra and ventral tegmental area.
H2R mainly mediates the neuronal excitability elicited by histamine.
Histamine induced excitatory response in globus pallidus neurons and
cerebellar dentate nucleus neurons, as well as cerebellar Purkinje cells
through H2 receptors (Chen, Wang, Yung, Chan & Chow, 2005; Qin et al.,
2011; Tian, Wen, Li, Zuo & Wang, 2000), which linked to intracellular
G-protein-adenylate cyclase (AC)- PKA signaling pathway (Chen, Wang,
Yung, Chan & Chow, 2005). Additionally, histamine elicits excitatory
response in the lateral vestibular nucleus neurons in rats, which is
co-mediated by the
H2R
linked-hyperpolarization-activated cyclic nucleotide-gated (HCN)
channels and K+ channels (Li et al., 2016).
Many studies have confirmed that activation of both postsynaptic H1R and
H2R co-mediates histamine induced-neuron excitability in several kinds
of neurons. For instance, histamine excites dopamine D1 and D2
receptor-expressing striatal GABAergic medium spiny projection neurons,
nucleus basalis cholinergic neurons, substantia nigra pars reticulate
inhibitory projection neurons, GABAergic ventral pallidum neurons,
superior vestibular nuclear neurons, and inferior vestibular nucleus
neurons via postsynaptic H1R and H2R (Ji et al., 2018; Khateb, Fort,
Pegna, Jones & Mühlethaler, 1995; Peng, Zhuang, He, Zhu & Wang, 2013;
Zhou, Xu, Zhao, LeDoux & Zhou, 2006; Zhuang, Wu, Wu, Zhu & Wang, 2013;
Zhuang et al., 2018). In medial vestibular nuclear neurons, histamine
induces strong postsynaptic excitatory action by Na⁺-Ca²⁺ exchangers
coupled to H1R and HCN linked to H2R (Zhang, Yu, Zhuang, Peng, Zhu &
Wang, 2013). Additionally, histamine facilitates GABAergic transmission
in the rat entorhinal cortex through H1R and H2R by activating
Na+ permeable cation channels and inhibiting inward
rectifier K+ channels (Cilz & Lei, 2017).