G protein-coupled receptors--recent advances.

Abstract

The years 2000 and 2007 witnessed milestones in current understanding of G protein-coupled receptor (GPCR) structural biology. In 2000 the first GPCR, bovine rhodopsin, was crystallized and the structure was solved, while in 2007 the structure of β2-adrenergic receptor, the first GPCR with diffusible ligands, was determined owing to advances in microcrystallization and an insertion of the fast-folding lysozyme into the receptor. In parallel with those crystallographic studies, the biological and biochemical characterization of GPCRs has advanced considerably because those receptors are molecular targets for many of currently used drugs. Therefore, the mechanisms of activation and signal transduction to the cell interior deduced from known GPCRs structures are of the highest importance for drug discovery. These proteins are the most diversified membrane receptors encoded by hundreds of genes in our genome. They participate in processes responsible for vision, smell, taste and neuronal transmission in response to photons or binding of ions, hormones, peptides, chemokines and other factors. Although the GPCRs share a common seven-transmembrane α-helical bundle structure their binding sites can accommodate thousands of different ligands. The ligands, including agonists, antagonists or inverse agonists change the structure of the receptor. With bound agonists they can form a complex with a suitable G protein, be phosphorylated by kinases or bind arrestin. The discovered signaling cascades invoked by arrestin independently of G proteins makes the GPCR activating scheme more complex such that a ligand acting as an antagonist for G protein signaling can also act as an agonist in arrestin-dependent signaling. Additionally, the existence of multiple ligand-dependent partial activation states as well as dimerization of GPCRs result in a ‘microprocessor-like’ action of these receptors rather than an ‘on-off’ switch as was commonly believed only a decade ago.

Presynaptic long-term depression mediated by Gi/o-coupled receptors

“…It is not as simple as a G i/o -GPCR belonging to a specific structural class. For example, class A/rhodopsin GPCRs, such as CB1R, 5-HT1bR, and the opioid receptors and the class C/glutamate GPCRs, the group II/III mGluRs [10], can induce LTD following activation. Even within classes there appears to be divergence; activation of certain presynaptic G i/o -GPCRs, such as CB1R, is known to induce either STD or LTD, depending on the induction protocol that is delivered [100].…”

“…G αs stimulates adenylyl cyclase (AC), G αi inhibits AC, G αq/11 activates phospholipases and subsequently intracellular Ca 2+ levels, whereas G α12/13 operates through more complex pathways [10]. Specific GPCRs are referred to as coupling to a specific G α class, but this preferred coupling is mutable [10].…”

“…G αs stimulates adenylyl cyclase (AC), G αi inhibits AC, G αq/11 activates phospholipases and subsequently intracellular Ca 2+ levels, whereas G α12/13 operates through more complex pathways [10]. Specific GPCRs are referred to as coupling to a specific G α class, but this preferred coupling is mutable [10]. G βγ protein subunits couple to ion channels such as voltage dependent Ca 2+ channels (Cav2, VDCCs) and the G protein-coupled Kir3 class of potassium channels (GIRKs) [11].…”

“…G βγ also directly interacts with vesicular fusion machinery (consisting of SNARE, Ca 2+ sensing and regulatory proteins) [11] as well as kinases, phospholipases, and even AC [12]. Scaffolding proteins such as beta-arrestin unite GPCRs with other signaling proteins such as kinases that provide additional routes for GPCRs to influence cellular function [10]. …”

Heterotrimeric G proteins interact with defense-related receptor-like kinases in Arabidopsis

“…Their plasma membrane localization suggest that, like their animal counterparts, plant G proteins mediate the initial stages of signaling connecting agonist bound receptors to intracellular effectors (Adjobo-Hermans et al, 2006;Zeng et al, 2007). However, unlike animals, plants have very few candidate GPCRs, and their status as bona fide GPCRs is still debated (Fredriksson and Schioth, 2005;Johnston and Siderovski, 2007;Latek et al, 2012;Urano et al, 2013). The mildew resistance locus O (MLO) 7TM receptor-like proteins were speculated to be a family of plant GPCRs, however, recent reports demonstrate that MLOs and G-proteins function independently (Consonni et al, 2006;Lorek et al, 2013).…”