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).