2.2 H1R and neural excitability
The human H1R gene is located on chromosome 3, which encodes a member of the 7-transmembrane, G-protein-associated receptor family (486-491 amino-acids). H1R is coupled with Gq/11 protein and phospholipase C, which in turn hydrolyses phosphatidyl-4, 5-biphosphate to form second messenger, diacylglycerol (DAG) and phosphatidyl inositol-4, 5-biphosphate (IP3) (Leurs, Traiffort, Arrang, Tardivel-Lacombe, Ruat & Schwartz, 1994). DAG activates phosphokinase C (PKC), which in turn induces mitogen-activated protein kinase (MAPK) activation, which involves in neuron synaptic plasticity (Yamamoto et al., 2012). The DAG and IP3 promote calcium release from the endoplasmic reticulum into the cytoplasm. In addition, H1R activation subsequently leads to formation of arachidonic acid (AA) and cyclic guanosine monophosphate (cGMP). The H1R is widely distributed in the brain, including thalamus, cortex, basal forebrain, raphe nuclei, hypothalamus, septal nuclei, amygdala, hippocampus, locus corelus, nucleus accumbens, and nucleus tractus solitaries as well as cerebellum. The central H1R is mainly corresponding for the side effects of antihistamine drugs.
Most of H1R mediates either excitatory or inhibitory response of histamine in neurons, depending on different brain regions. For example, through H1R, histamine elicits neuronal excitability in the ventromedial hypothalamus and GABAergic neurons in both substantia nigra and ventral tegmental area, and the K+ channel is involved in that (Korotkova, Haas & Brown, 2002; Zhou, Lee, Devidze, Zhang, Kow & Pfaff, 2007). However, H1R also negatively regulate the neuronal excitability. For instance, H1R decreases cell excitability of hippocampal pyramidal neurons through activation of K+channels by increase of Ca2+ (Selbach, Brown & Haas, 1997). Similarly, H1R antagonist led to membrane potential depolarization in superior cervical ganglion neurons via inhibiting KCNQ/M K+ channel (Liu, Zhang, Wang, Zhang & Zhang, 2008).