Receptor-guanine nucleotide interactions

In other cell types, guanine nucleotides interact with a guanine nucleotide subunit (G- or Ng-subunit) to translate receptor stimulation into increased adenylate cyclase activity (12.) Cholera toxin inhibits a specific GTPase on this guanine nucleotide subunit and thereby increases adenylate cyclase activity (13.). In dispersed cells from the bovine parathyroid gland, cholera toxin markedly increases cAMP formation and causes a 3 to 10-fold increase in the apparent affinity cf dopamine for its receptor (as determined by cAMP accumulation or IR-PTH secretion (J y.). The effects of guanine nucleotides and cholera toxin on cAMP accumulation in parathyroid cells result from interactions with the guanine nucleotide subunit in this cell. 

Figure 1. Simplified schematic of receptor-mediated signal transduction in neutrophils. Binding of ligand to the receptor activates a guanine-nucleotide-binding protein (G protein), which then stimulates phospholipase C. Phosphatidylinositol 4,5-bis-phosphate is cleaved to produce diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). DAG stimulates protein kinase C. IP3 causes the release of Ca from intracellular stores, which results in an increase in the cytosolic Ca concentration. This increase in Ca may stimulate protein kinase C, calmodulin-dependent protein kinases, and phospholipase A2. Protein phosphorylation events are thought to be important in stimulating degranulation and oxidant production. In addition, ionic fluxes occur across the plasma membrane. It is possible that phospholipase A2 and ionic channels may be governed by G protein interactions. ...

The a subunit has two other important functional domains in addition to the P-binding domain. First, the a subunit interacts with the receptor through a domain that includes the last five amino acids of the C-terminus (Figure 7.3). Second, it bears the guanine nucleotide binding pocket and... 

When the receptor interacts with its associated G protein, the conformation of the guanine-nucleotide-binding site is altered. The subunits then dissociate, and a phosphatidylinositol-specific phospholipase C (PI-PLC) is activated [5]. The subsequent hydrolysis of phosphatidylinositol bisphosphate then produces inositol triphosphate (IP3) and diacylglycerol (DAG), which are known to be secondary messengers. For example, the water soluble IP3 is released into the cell where its ultimate targets are the calcium storage organelles from which Ca2+ is released [3]. The presence of DAG in cells is known to activate the cellular enzyme protein kinase C (PKC) [6, 7], which phosphorylates a number of cellular... 

MacNulty EE, McClue SJ, Carr IC, Jess T, Wakelam MJ, Milligan G (1992) a2-C10 adrenergic receptors expressed in rat 1 fibroblasts can regulate both adenylylcy-clase and phospholipase D-mediated hydrolysis of phosphatidylcholine by interacting with pertussis toxin-sensitive guanine nucleotide-binding proteins. J Biol Chem 267 2149-2156... 

Vos MD, Ellis CA, Bell A, Birrer MJ, Clark GJ (2000) Ras uses the novel tumor suppressor RASSFl as an effector to mediate apoptosis. J Biol Chem 275 35669-35672 Voss T, Wallner E, Czernilofsky AP, Freissmuth M (1993) Amphipathic alpha-helical structure does not predict the ability of receptor-derived synthetic peptides to interact with guanine nucleotide-binding regulatory proteins. J Biol Chem 268 4637-4642... 

The G proteins with which G protein-coupled receptors interact are heterotrimeric complexes composed of a, P, and y subunits. In its inactive state, the G-protein a subunit is bound to GDP and associates with a Py dimer. Upon receptor activation, the a subunit opens its guanine nucleotide binding site and releases its bound GDP, allowing GTP, which is present in higher concentrations in the cell, to bind in its place. The GTP-bound a subunit has a lower affinity for the Py dimer and dissociates from it, freeing both the a sub-... 

Hu P, Margolis B, Skolnik EY et al. Interaction of phosphatidylinositol 3-kinase-associated p85 with epidermal growth factor and platelet-derived growth factor receptors. Mo/ Cell Biol 1992 12 981-990. Li N, Batzer A, Daly R et al. Guanine-nucleotide-releasing factor hSosl binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature 1993 363 85-88. 

The signaling process appears to involve a series of molecular ON and OFF switches that are driven by binding interactions between components of the ternary complex, guanine nucleotides, and effectors (Vetter and Wittinghofer, 2001). In cells, the transient interaction of a ligand-activated receptor with a heterotrimeric G protein causes the rapid ejection of an otherwise stably bound GDP nucleotide from the nucleotide-binding... 

Yamada, T., Ohoka, Y., Kogo, M., and Inagaki, S. (2005). Physical and functional interactions of the lysophosphatidic acid receptors with PDZ domain-containing Rho guanine nucleotide exchange factors (RhoGEFs)./ Biol. Chem. 280,19358-19363. 

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