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    • br Introduction G protein coupled receptors GPCRs represent

    2021-10-13


    Introduction G-protein coupled receptors (GPCRs) represent one of the largest family of receptors involved in cell membrane signal transduction and have become one of the leading therapeutic targets worldwide (Chakraborty and Chattopadhyay, 2015; Bouvier, 2001; Sriram and Insel, 2018). GPCRs signalling produces a diverse array of functions including neurotransmission, cellular metabolism, cell differentiation and also inflammatory and immune responses (Betke et al., 2012; Steury et al., 2017; Weiss et al., 2017; Sebastiao and Ribeiro, 2009). Classically, GPCRs were assumed to function as monomeric structures. However, the concept of homodimerization, heterodimerization and even higher-order oligomerization of GPCRs has emerged over the past three decades (Kern et al., 2015; Chen et al., 2015; Schellekens et al., 2013d; Wellman and Abizaid, 2015; Agnati et al., 1980; Borroto-Escuela et al., 2017). Accumulating studies show that the GPCR heteromerization significantly impact downstream signalling pathways, for example, via changes in G protein coupling, ligand-mediated allostery, agonist-promoted GPCR bryostatin australia or co-internalization, all with marked consequences for biological functionality (Cudmore et al., 2012; Rocheville, 2000; Borroto-Escuela et al., 2013; Siddiquee et al., 2013; Schellekens et al., 2013a). The oxytocin receptor (OTR), a class A GPCR, is a 7-transmembrane receptor expressed widely throughout the periphery and central nervous system in areas such as the reproductive system (Kimura et al., 2013; Thackare et al., 2006) and centrally in areas of the hippocampus, hypothalamus and amygdala (Raam et al., 2017; Calcagnoli et al., 2014; Gimpl and Fahrenholz, 2001). The OTR is known for its diverse function upon activation with its endogenous ligand oxytocin. Upon binding of oxytocin, OTR-mediated signalling occurs primarily through the Gαq alpha subunit (Gαq), but is also known to signal through the Gαi alpha subunit (Busnelli and Chini, 2018). Activation of Gαq subunit results in a cascade of events leading to inositol trisphosphate (IP3) and diacylglycerol (DAG) synthesis (Tuteja, 2009). Activated IP3 subsequently interacts with its receptor and combined activation of the ryanodine receptor results in an influx of calcium (Ca2+) from intracellular stores within the endoplasmic reticulum (Murtazina et al., 2011). This is followed by allosteric activation of protein kinase C (PKC) by DAG (Huang, 1989). Interestingly, Ca2+ release is also known to play an important role in the activation of specific isoforms of PKC (Luo and Weinstein, 1993). The release of Ca2+ from intracellular stores has a wide array of functions (Berridge, 2002), including regulation of protein synthesis (Viero et al., 2010; Wong et al., 1993), cell proliferation and cell death (Capiod, 2011; Pinton et al., 2008), memory and learning (Nakamura et al., 2017) and membrane trafficking (Li et al., 2013). Interestingly, the endogenous OTR ligand, oxytocin is also known to regulate and interact with other central hormones (Crowley et al., 1991; Jorgensen et al., 2003), including the gut-derived hormone, ghrelin which is critically involved in appetite regulation and feeding (Howick et al., 2017; Schellekens et al., 2010; Pradhan et al., 2013). Increases in oxytocin levels have been shown to reduce circulating ghrelin levels in humans (Vila et al., 2009), while contrastingly oxytocin administration is known to enhance the secretion of ghrelin in vitro in a ghrelin expressing cell line (Iwakura et al., 2011). Furthermore, in a neurohypophyseal diabetes cell line, addition of ghrelin resulted in increased secretion of oxytocin (Gálfi et al., 2016). Such crosstalk between oxytocinergic and ghrelinergic systems may indicate a possible interaction between the OTR and the ghrelin receptor type 1a (GHSR). The ghrelinergic system consist of the neuroendocrine peptide, ghrelin which signals via the ghrelin receptor type 1a, referred throughout this manuscript as GHSR, and a truncated ghrelin type 1b receptor (Albarran-Zeckler and Smith, 2013). The GHSR, similarly to the OTR, also belongs to the class A GPCRs and is known to primarily signal through the Gαq protein, which results in the release of Ca2+ from intracellular stores (Schellekens et al., 2013c). The GHSR is also known to activate other signalling pathways, including the Gαi-dependent signalling pathway, which inhibits cyclic adenosine monophosphate (cAMP), a regulatory subunit of protein kinase A (PKA) (M'kadmi et al., 2015). Moreover, the GHSR is known to activate the Gα12/13 subunit, which subsequently regulates the serum response element associated with transcriptional activity. Interestingly, different GHSR ligands have also been shown to have functional selectivity and biased signalling, which may result in more selective functional outputs when targeting the GHSR (Holst et al., 2004; Sivertsen et al., 2011; M'kadmi et al., 2015; Ramirez et al., 2018).