Heterotrimeric G‐proteins: a short history

Abstract

Some 865 genes in man encode G-protein-coupled receptors (GPCRs). The heterotrimeric guanine nucleotide-binding proteins (G-proteins) function to transduce signals from this vast panoply of receptors to effector systems including ion channels and enzymes that alter the rate of production, release or degradation of intracellular second messengers. However, it was not until the 1970s that the existence of such transducing proteins was even seriously suggested. Combinations of bacterial toxins that mediate their effects via covalent modification of the a-subunit of certain G-proteins and mutant cell lines that fail to generate cyclic AMP in response to agonists because they either fail to express or express a malfunctional G-protein allowed their identification and purification. Subsequent to initial cloning efforts, cloning by homology has defined the human G-proteins to derive from 35 genes, 16 encoding a-subunits, five b and 14 g. All function as guanine nucleotide exchange on-off switches and are mechanistically similar to other proteins that are enzymic GTPases. Although not readily accepted initially, it is now well established that b/g complexes mediate as least as many functions as the asubunits. The generation of chimeras between different a-subunits defined the role of different sections of the primary/secondary sequence and crystal structures and cocrystals with interacting proteins have given detailed understanding of their molecular structure and basis of function. Finally, further modifications of such chimeras have generated a range of G-protein a-subunits with greater promiscuity to interact across GPCR classes and initiated the use of such modified G-proteins in drug discovery programmes.

The Mg2+ and Mg2+-Nucleotide-Regulated Channel-Kinase TRPM7

“…This is presumably due to the fact that TRPM7 binds to and inhibits PLC (Runnels et al 2001). The overexpression of Gq-coupled receptors faces the problem of G protein promiscuity (Xiao 2000;Milligan and Kostenis 2006), where receptors may couple to other G proteins and activate signaling pathways unrelated to PLC. Another potential problem is the fact that the cells under investigation can have endogenous receptors that are activated in parallel with the overexpressed receptors, which is the case for muscarinic receptors, as some of them couple to PLC (M1, M3, M5) whereas others couple to Gi (M2, M4).…”

CXCL1 Inhibits Airway Smooth Muscle Cell Migration through the Decoy Receptor Duffy Antigen Receptor for Chemokines

“…2A) or siRNA knockdown (Fig. 2B) of CXCR1 and CXCR2 receptors, or to the effect of Ptx, which inhibits Gai signaling (40) (Fig. 2C), suggesting that it is unlikely for CXCR1, CXCR2, and other Gai-protein-coupled receptors (Gai-PCRs) to be involved in mediating CXCL1 inhibition of ASMC migration.…”

Opening the “Black Box”: The Genetic and Biochemical Basis of Eye Evolution

“…Following photo-activation in some animal eyes, nearby proteins must act to restore opsin and its chromophore to the original state before new photons can initiate a response. G-protein: heterotrimeric signaling molecules G-proteins represent an ancient (older than animals) family of proteins that have diversified modestly relative to GPCRs with which they interact (Milligan and Kostenis 2006). While nearly all light-sensing animals rely on these G-proteins for phototransduction (as well as a host of other GPCR-mediated responses), different opsins will preferentially bind different classes of the Gα subunit.…”