The H R couples to G i o proteins and

The H3R couples to Gαi/o proteins, and hence its stimulation leads to inhibition of adenyalate cyclases, diminishing the level of cyclic AMP (cAMP) with the subsequent reduction in downstream signaling pathways such as protein kinase A (PKA) activation and cAMP-responsive element binding protein (CREB)-induced gene transcription. The Gβγ complexes of Gαi/o proteins inhibit the opening of voltage-activated calcium channels, thereby reducing neurotransmitter release (Nieto-Alamilla, Marquez-Gomez, Garcia-Galvez, Morales-Figueroa, & Arias-Montano, 2016). Like other histamine receptors, H3R forms receptor heterodimers shown for dopamine D1 and D2 receptors so far (Ferrada et al., 2008; Vohora & Bhowmik, 2012). Thereby, decreased affinity of D2 receptor ligands could be observed in presence of H3R agonists in vitro as well as potentiation of D1 and D2 receptor mediated locomotor activity by application of the H3R inverse agonist/antagonist thioperamide (Ferrada et al., 2008). Other D609 australia proteins activated by H3R stimulation include mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3K) and phospholipase A2 (PLA2) producing arachidonic acid. MAPK and PI3K signaling pathways are associated with the phosphorylation of extracellular signal-regulated kinases (ERKs) and protein kinase B (PKB), respectively, and the latter inhibits glycogen synthase kinase-3β (GSK-3β). H3R activation also inhibits the activity of the Na+/H+ exchanger (Bhowmik, Khanam, & Vohora, 2012; Leurs et al., 2005). Fig. 1 illustrates the different signaling pathways elicited or modulated by H3R activation. Collectively, the modulation of the release of histamine and other neurotransmitters through H3R activation could be linked to several neurological disorders such as sleep disorders like narcolepsy, Alzheimer's disease, attention deficit and hyperactivity disorder (ADHD), Parkinson's disease, schizophrenia, multiple sclerosis, Tourette's syndrome, pain, obesity etc (Bhowmik et al., 2012; Brioni, Esbenshade, Garrison, Bitner, & Cowart, 2011; Gemkow et al., 2009; Lin, Sergeeva, & Haas, 2011; Passani et al., 2017; Passani & Blandina, 2011; Provensi, Blandina, & Passani, 2016; Shan, Bao, & Swaab, 2015). Fig. 2 shows the clinical trials reported for H3R antagonists/inverse agonists in relation to neurological disorders and other diseases.
Histamine has an important role in the light/dark cycle in which histamine levels increase during wakefulness to decline to the baseline level during sleep (Brioni et al., 2011; Lin et al., 2011; Meredith & Tony, 2011). Therefore, enhanced histamine neurotransmission due to H3R blockade improves wakefulness and vigilance in individuals suffering from narcolepsy during daytime (Gondard et al., 2013). Narcolepsy is defined as uncontrollable excessive sleepiness and irregular onset of rapid eye movement (REM) sleep during the daytime that affect the quality of life. Episodes of sudden loss of muscle control (known as cataplexy) are experienced by most narcoleptic individuals (Calik, 2017). The wake promoting effect of H3R antagonists has been well documented and several studies have shown that antagonizing H3R receptors results in increased histamine levels, which in turn augment the activation of post-synaptic H1 receptors leading to enhanced wakefulness (Broderick & Masri, 2011; Gondard et al., 2013; Lin et al., 2011; Parmentier et al., 2007; Thakkar, 2011). The advantage of H3R antagonists over classical psychostimulants is the lack of locomotor activity, behavioral excitation, and sleep rebound (Berlin et al., 2011; Broderick & Masri, 2011; Lin et al., 2011). Alzheimer's disease (AD), the most prevalent form of dementia, is a neurodegenerative disorder with cognitive deficit and memory impairment in the geriatric population. Although the cholinergic system is mainly targeted for enhancing acetylcholine levels by inhibiting its enzymatic degradation, the role of H3Rs in modulating acetylcholine release should not be neglected. Nonetheless, the role of the histaminergic system in the pathophysiology of AD is not completely understood and some discrepancies still exist. For example, some reports indicate hyperactivity of the CNS histaminergic system, whereas other studies reveal a loss of histaminergic neurons in AD (Shan et al., 2015; Vohora & Bhowmik, 2012). However, recent reports are indicative of H3R-mediated regulation of acetylcholine release leading to elevated levels in cortex and hippocampus (Brioni et al., 2011; Esbenshade et al., 2008; Sadek, Saad, Sadeq, Jalal, & Stark, 2016). On the other hand, H3R antagonism increases CREB and GSK3β phosphorylation resulting in improvement of cognitive processes (Brioni et al., 2011; Leurs et al., 2005; Sadek, Saad, Sadeq, et al., 2016; Sander, Kottke, & Stark, 2008).