Receptor-Mediated Activation of Heterotrimeric G-Proteins: Current Structural Insights (original) (raw)

2007, Molecular Pharmacology

G-protein-coupled receptors (GPCRs) serve as catalytic activators of heterotrimeric G-proteins (G␣␤␥) by exchanging GTP for the bound GDP on the G␣ subunit. This guanine nucleotide exchange factor activity of GPCRs is the initial step in the G-protein cycle and determines the onset of various intracellular signaling pathways that govern critical physiological responses to extracellular cues. Although the structural basis for many steps in the G-protein nucleotide cycle have been made clear over the past decade, the precise mechanism for receptor-mediated Gprotein activation remains incompletely defined. Given that these receptors have historically represented a set of rich drug targets, a more complete understanding of their mechanism of action should provide further avenues for drug discovery. Several models have been proposed to explain the communication between activated GPCRs and G␣␤␥ leading to the structural changes required for guanine nucleotide exchange. This review is focused on the structural biology of G-protein signal transduction with an emphasis on the current hypotheses regarding G␣␤␥ activation. We highlight several recent results shedding new light on the structural changes in G␣ that may underlie GDP release. Many key extracellular signals, including hormones, neurotransmitters, growth factors, and sensory stimuli, relay information intracellularly by activation of plasma membrane-bound receptors. The largest class of such receptors is the superfamily of heptahelical G-protein-coupled receptors (GPCRs). In many genomes, GPCRs are encoded by the largest gene family; in humans, Ͼ1% of the genome is dedicated to producing hundreds of these critical signal detectors (Takeda et al., 2002; Fredriksson et al., 2003). Genetic studies have highlighted the physiological importance of GPCRs, with knockout models revealing pathological phenotypes involving the cardiovascular, nervous, endocrine, and sensory systems (Rohrer and Kobilka, 1998; Yang et al., 2002; Karasinska et al., 2003). Several hereditary diseases have also been linked to mutations within the genes encoding specific GPCRs (Spiegel and Weinstein, 2004). Indeed, GPCRs represent a major therapeutic target, giving rise to the largest single fraction of the prescription drug market, with annual sales of several billion dollars (Overington et al., 2006). Therefore, a complete mechanistic understanding of how GPCRs communicate extracellular signals into the cell would be extremely valuable for the continued development of novel therapeutics that target this family of receptors and the signaling cascades they modulate. G-Protein Signaling and the Guanine Nucleotide Cycle GPCRs transduce signals by activating heterotrimeric Gproteins that normally exist in an inactive state of G␣-GDP bound to G␤␥ subunits (Fig. 1). Agonist activation of GPCRs induces a conformational change within the receptor, which subsequently catalyzes the exchange of GDP for GTP on the G␣ subunit (Gilman, 1987). In this way, GPCRs serve as guanine nucleotide exchange factors (GEFs) for G␣-GDP/G␤␥ complexes (Fig. 1). Although the exact mechanism by which GPCRs exert their GEF activity remains to be fully eluci-The writing of this review was made possible by generous funding support (F32-GM076944, R01-GM062338, and R01-GM074268) from the National Institute of General Medical Sciences. Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.