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  • The human serotonin hydroxytryptamine HT receptor family con


    The human serotonin (5-hydroxytryptamine; 5-HT) receptor family consists of 14 receptor subtypes to date, which are primarily G protein-coupled receptors (GPCRs) with 5-HT3 being the sole ligand-gated ion channel (Alexander et al., 2017). These receptors are widely distributed in the central and peripheral nervous systems and other tissues, where they perform neurotransmission and signaling via serotonin: their cognate ligand (“Tissue expression of HTR2A -The Human Protein Atlas,”; Nichols and Nichols, 2008). Serotonin and its receptors play important roles in various peripheral tissues as well. The 5-HT2A receptor is an important 7TM receptor of the serotonergic neuromodulatory system and has been implicated in many psychiatric disorders. It belongs to group A GPCRs, which are rhodopsin-like membrane proteins. These bind to G-proteins intracellularly and have seven transmembrane helices, with the ligand binding site within the transmembrane regions (Almaula et al., 1996, Shapiro et al., 2000). Various techniques such as in-situ hybridization, radioligand binding assays, RT-PCR and antibody staining have been used to determine that 5-HT2A is expressed in areas of the CNS such as the neocortex, the hippocampus, subiculum, the ventral tegmental area (VTA), substantia nigra (SN), the olfactory bulb, and dorsal horns of the spinal cord (Andrade et al., 2015). Among peripheral organs, it is expressed in a wide variety of tissues, including the coronary and renal arteries, the epicardium, smooth muscle cells, peripheral lymphocytes and platelets, spleen, as well as the uterus (Cordeaux et al., 2009, Andrade et al., 2015). 5-HT receptors influence various processes and are implicated in a wide range of functions: from hallucinations to learning and memory, and in disorders such as depression and schizophrenia (Nichols, 2004, Zhang and Stackman, 2015). Consequently, they have proven to be one of the primary targets for several drugs, including many antidepressants, anorectics, and therapeutic (antipsychotic) drugs such as clozapine and risperidone (Soudijn, 1997, Nichols, 2004, Rowland et al., 2008, Meltzer and Massey, 2011). A variety of ligands binds to the serotonin 2A receptor (5-HT2A), including biogenic amines, synthetic hallucinogenic tryptamines, as well as the recreational drugs: psilocin, psilocybin, lysergic YM178 diethylamide (LSD), and the hallucinogens: 2,5-dimethoxy-4-iodoamphetamine (DOI) and 2,5-Dimethoxy-4-bromoamphetamine (DOB) (Woodward et al., 1992, Ronken and Olivier, 1997, Roth, 1998, Nichols, 2004). Some effects of these non-endogenous 5-HT2A ligands, on subcellular signaling pathways downstream of the receptor, have also been reported (González-Maeso et al., 2003, Bhattacharyya et al., 2006). This receptor also plays a role in peripheral processes such as liver regeneration, hemostasis, the contraction of smooth muscle walls, and inflammation (Ronken and Olivier, 1997, Janssen et al., 2002, Lesurtel et al., 2006, Yu et al., 2008, Bampalis et al., 2011, Abrol et al., 2013). Serotonin, the cognate ligand, activates the PLC-inositol 1,4,5-trisphosphate-protein kinase C pathway through 5-HT2A, leading to the release of IP3 as the second messenger and the accumulation of calcium intracellularly (Raymond et al., 2001, Raote et al., 2007). This is accepted as the canonical signaling pathway of the receptor. Some GPCRs display a phenomenon referred to as “functional selectivity” or “ligand biased agonism”, which is characterized by ligands binding to the receptor, activating downstream pathways or/and modulating intracellular transduction cascades differentially (Kenakin, 1995a, Kenakin, 1995b, Urban et al., 2007). This functional selectivity possibly arises out of “GPCR pleiotropy”, or the “structural flexibility” of a receptor to occupy a particular conformation space biased by the interacting ligand, which may or may not be different from the steady-state conformation space (Kenakin, 2004, Abrol et al., 2013). Therefore different signaling cascades/pathways are thought to be set up by the receptors by coupling to, or interacting with different signaling partners. Different ligands may uniquely modulate sets (subsets) of signaling pathways by stabilizing/biasing/preferring specific receptor conformations. Thus, different ligands acting at a single receptor can produce differential effects: either by activation of diverse signaling cascades with varying efficacies or by activating entirely unique cascades, which poses a challenge in classifying a ligand as purely an agonist or an antagonist (Kenakin et al., 2012). Work with the rat 5-HT2A has shown that this receptor also shows functional selectivity with respect to its internalization and recycling (Raote et al., 2013). Depending on the ligand, the 5-HT2A receptor has been shown to preferentially activate either of the two pathways most associated with it: the PLC-PKC pathway, or the arachidonic acid (AA) pathway (Berg et al., 1998). Involvement of 5-HT2A has been reported in cell-adhesion interactions such as platelet aggregation and ectoderm extension (Colas et al., 1999, Nakamura et al., 2000, Kubacka et al., 2018). Studies also show a correlation between 5-HT2A polymorphism (T102C) and increased platelet aggregation (Shimizu et al., 2003). 5-HT2A is also involved in certain adhesion dependent phenomena such as the activation, migration, and differentiation of cardiac fibroblasts (Yabanoglu et al., 2009). However, the role of its ligands in cell-substrate adhesion is yet to be studied. The serotonin 2A receptor also plays an important role in the neuromodulatory functions of serotonin, especially the regulation of dopamine (DA) neuronal activity in the brain (De Deurwaerdère and Di Giovanni, 2017). Activation of 5-HT2A leads to increased dopaminergic function and release of dopamine in the cortex. In the present study we demonstrate that DA is able to activate 5-HT2A and can bring about specific cellular and receptor behavior different from that seen with serotonin. We have established that the ‘functional selectivity’ observed is dependent on certain cytoplasmic residues within the receptor which have been mutated to confirm their roles.