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  • GABAB receptor is associated with brain and behavioral disea

    2024-04-02

    GABAB receptor is associated with E-64-c and behavioral diseases, including epilepsy, spasticity, anxiety and neuropathic pain (Bettler et al., 2004, Bowery et al., 2002, Froestl, 2010). Baclofen, a clinical drug and selective GABAB receptor agonist, is used to treat muscle spasticity in patients with multiple sclerosis, cerebral palsy, and spinal cord injury (Bettler et al., 2004, Bowery et al., 2002, Froestl, 2010). Knowledge of the GABAB receptor structure has provided a detailed understanding of how current drugs act on the receptor, and will facilitate the design of better candidates for desired regulation. GABAB receptor is an obligatory heterodimer, with two subunits specialized for different functions (Jones et al., 1998, Kaupmann et al., 1998, Kuner et al., 1999, Martin et al., 1999, Ng et al., 1999, White et al., 1998). The first subunit, known as GABAB1, binds orthosteric ligands (Kaupmann et al., 1997, Malitschek et al., 1999), while the second, GABAB2, couples with G protein (Duthey et al., 2002, Galvez et al., 2001, Havlickova et al., 2002, Margeta-Mitrovic et al., 2001, Monnier et al., 2011, Pin et al., 2004a, Robbins et al., 2001). In addition, a subfamily of the potassium channel tetramerization-domain (KCTD) proteins interact with GABAB2, and act as auxiliary subunits of the receptor to modulate the kinetics of G protein signaling (Bartoi et al., 2010, Schwenk et al., 2010). Each GABAB receptor subunit consists of three domains: an N-terminal extracellular domain, a seven-helix transmembrane (TM) domain, and a cytoplasmic tail (Pin and Bettler, 2016) (Fig. 1A). Of these domains, three-dimensional structures have been solved for the extracellular domain and a fragment of the intracellular domain (Blein et al., 2004, Burmakina et al., 2014, Geng et al., 2012, Geng et al., 2013). The ectodomain structure has also been determined in multiple conformations, allowing us to describe the heterodimer interfaces, receptor-ligand interactions, and conformational changes associated with receptor activation (Geng et al., 2013). What remains unknown is the conformational dynamics of GABAB receptor TM domain, and how the individual domains function in an intact receptor. The structures of the full-length receptor in multiple functional states would be required to address these questions. Currently, additional insights on GABAB receptor function can be obtained by examining the comparable structures within its related group of GPCRs, called the class C family. GPCRs are divided into four main classes (A, B, C and F) based on the sequence homology of their TM domains (Lagerstrom and Schioth, 2008). Class C GPCRs mediate key biological phenomena, including excitatory and inhibitory neurotransmission, calcium homeostasis, taste and smell (Pin et al., 2003, Pin et al., 2004b). The class C GPCRs are unique in that they require dimerization to function (Pin et al., 2003, Pin et al., 2004b). Within this family, GABAB receptor and taste receptors (TAS1R) are obligatory heterodimers (Jones et al., 1998, Kaupmann et al., 1998, Kuner et al., 1999, Nelson et al., 2001, Nelson et al., 2002, White et al., 1998). While metabotropic glutamate (mGlu) receptors and calcium-sensing (CaS) receptor are traditionally considered to function as homodimers (Bai et al., 1998, El Moustaine et al., 2012, Okamoto et al., 1998, Pidasheva et al., 2006, Ray et al., 1999, Romano et al., 1996, Tsuji et al., 2000, Ward et al., 1998, Zhang et al., 2001), they have recently been discovered to assemble into heterodimers with other class C and class A GPCRs (Doumazane et al., 2011, Gama et al., 2001, Gonzalez-Maeso et al., 2008, Moreno Delgado et al., 2017, Pandya et al., 2016, Yin et al., 2014). Like GABAB receptor, each class C receptor is characterized by a large extracellular domain in addition to the canonical seven-helix TM domain (Pin et al., 2003, Pin et al., 2004b) (Fig. 1B). This extracellular domain has 500–600 amino acids, and contains the orthosteric ligand-binding site (Pin et al., 2003, Pin et al., 2004b). As of now, no full-length structure of any of these receptors has been solved, but structural information is available for the ectodomains of several family members (Blein et al., 2004, Geng et al., 2013, Geng et al., 2016, Geng et al., 2012, Kunishima et al., 2000, Muto et al., 2007, Nuemket et al., 2017, E-64-c Tsuchiya et al., 2002, Zhang et al., 2016) as well as the TM domains of two mGlu receptor subtypes (Christopher et al., 2015, Dore et al., 2014, Wu et al., 2014). In this review, we will summarize our current knowledge of GABAB receptor structure, and compare it with the known structures of class C GPCRs.