Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • ruthenium red The class C receptors also share a common agon

    2023-10-23

    The class C receptors also share a common agonist-binding mode. In all cases, an agonist induces VFT closure by forming intermolecular bonds with surface residues in both the LB1 and LB2 domains (Geng et al., 2013, Geng et al., 2016, Kunishima et al., 2000, Muto et al., 2007, Nuemket et al., 2017, Tsuchiya et al., 2002, Zhang et al., 2016). Key agonist-binding residues are conserved among the class C receptors. For example, a conserved Ser residue is responsible for anchoring the carboxylate of endogenous agonist in GABAB, mGlu, CaS and TAS1R2/TAS1R3 receptors (Geng et al., 2013, Geng et al., 2016, Kunishima et al., 2000, Muto et al., 2007, Nuemket et al., 2017, Tsuchiya et al., 2002, Zhang et al., 2016). An antagonist, on the other hand, depends on its bulky size to obstruct VFT closure, thereby keeping the ruthenium red in its open conformation (Geng et al., 2013, Tsuchiya et al., 2002).
    Allosteric ligand recognition Like other class C GPCRs, the activity of GABAB receptor can be regulated by allosteric modifiers (Brauner-Osborne et al., 2007, Conn et al., 2009, Kniazeff et al., 2011, Pin and Prezeau, 2007, Urwyler, 2011). These ligands usually fall under three categories: positive, negative and neutral. Positive allosteric modulators (PAMs) increase the efficacy of orthosteric ligands, while negative allosteric modulators (NAMs) decrease it (Brauner-Osborne et al., 2007, Conn et al., 2009, Kniazeff et al., 2011, Pin and Prezeau, 2007, Urwyler, 2011). At the same time, neutral or silent allosteric modifiers (SAMs) compete with PAMs and NAMs for specific allosteric sites, but do not alter receptor activity (Conn et al., 2009, Engers and Lindsley, 2013, Gregory et al., 2011, Urwyler, 2011). The first PAM of GABAB receptor, CGP7930, was discovered through drug screening (Urwyler et al., 2001). Since then, PAMs with different structural folds and improved potency have been developed, including GS39783, rac-BHFF, and BHF177 (Guery et al., 2007, Malherbe et al., 2008, Urwyler et al., 2003). Recently, a NAM called CLH304a, was reported to non-competitively inhibit GABAB receptor signaling (Chen et al., 2014). A neutral allosteric modulator of GABAB receptor has yet to be discovered. Studies employing mutations and chimeric receptors indicate that the known allosteric modulators of GABAB receptor bind within the TM domain of the G protein-coupling subunit, GABAB2 (Binet et al., 2004, Dupuis et al., 2006, Sun et al., 2016). Most PAMs do not activate full-length GABAB receptor on their own, but enhance the receptor response initiated by an agonist within the VFT (Brauner-Osborne et al., 2007, Kniazeff et al., 2011, Pin and Prezeau, 2007, Urwyler, 2011). Nevertheless, PAMs have been shown to induce G protein coupling when the extracellular domain of GABAB receptor is excised, implying that the unbound ectodomain constitutively maintains the inactive conformation of the receptor TM region (Binet et al., 2004). Fluorescence resonance energy transfer (FRET) experiments further revealed that the main GABAB receptor PAMs CGP7930, GS39783 and rac-BHFF differ in their modes of action, with CGP7930 and rac-BHFF displaying intrinsic agonist activity (Lecat-Guillet et al., 2017). However, the molecular basis of this variety of mechanisms is unknown since the PAM-binding site within the GABAB2 TM domain remains uncharacterized. On the other hand, the NAM CLH304a performs the opposite function, suppressing receptor stimulation by a GABAB receptor agonist (Chen et al., 2014). It also displays inverse agonist property by decreasing the basal activity of the receptor (Sun et al., 2016). In addition to allosteric interactions within the GABAB2 TM domain, GABAB receptor has been shown to be susceptible to allosteric modification by extracellular Ca2+ bound within the GABAB1 VFT module (Galvez et al., 2000, Wise et al., 1999). Ca2+ increases the affinity of GABA to the receptor, and enhances G protein activation as a result (Galvez et al., 2000, Wise et al., 1999). However, the allosteric effect of Ca2+ is not observed for baclofen (Galvez et al., 2000, Wise et al., 1999). Although mutational analysis points to a Ca2+-binding site within the GABAB1 VFT (Galvez et al., 2000, Wise et al., 1999), Ca2+ ion has yet to be identified in the known crystal structures of GABAB receptor extracellular domain (Geng et al., 2013).