Ligand-receptor-G protein

Wess, J. (1993) Mutational analysis of muscarinic acetylcholine receptors structural basis of ligand/receptor/G protein interactions. Ufe Sci 53 1447-1463. 

LRj is thought to be the signaling form of the receptor, able to activate G protein but not precoupled to it. The ternary complex of ligand-receptor-G-protein is not detected in typical binding studies of intact cells because it is very short-lived and only detectable in rapid mixing experiments [268]. That LRj is the signaling state is supported by the work of Jesaitis et al. [155] that shows the amount of oxidant response correlates with the amount of low affinity receptor on the cell surface. 

Lazareno, S., and Birdsall, N. J. M. (1995). Detection, quantitation, and verification of allosteric interactions of agents with labeled and unlabeled ligands at G protein-coupled receptors Interactions of strychnine and acetylcholine at muscarinic receptors. Mol. Pharmacol. 48 362-378. 

Cubic ternary complex model, a molecular model (J. Their. Biol 178, 151-167, 1996a 178, 169-182, 1996b 181, 381-397, 1996c) describing the coexistence of two receptor states that can interact with both G-proteins and ligands. The receptor/G-protein complexes may or may not produce a physiological response see Chapter 3.11. 

G-protein-coupled receptor kinases (GRKs) are a family of enzymes that catalyze the phosphorylation of threonine or serine residues on G-protein-coupled receptors. Characteristically, GRKs only phosphorylate the ligand-activated form of the receptors. Phosphorylation by GRKs usually leads to impaired receptor/G-protein coupling. 

Real-time spectroscopic methods can be used to measure the binding, dissociation, and internalization of fluorescent ligands with cell-surface receptors on cells and membranes. The time resolution available in these methods is sufficient to permit a detailed analysis of complex processes involved in cell activation, particularly receptor-G protein dynamics. A description of the kinetics and thermodynamics of these processes will contribute to our understanding of the basis of stimulus potency and efficacy. 

Muscarinic receptor activation causes inhibition of adenylyl cyclase, stimulation of phospholipase C and regulation of ion channels. Many types of neuron and effector cell respond to muscarinic receptor stimulation. Despite the diversity of responses that ensue, the initial event that follows ligand binding to the muscarinic receptor is, in all cases, the interaction of the receptor with a G protein. Depending on the nature of the G protein and the available effectors, the receptor-G-protein interaction can initiate any of several early biochemical events. Common responses elicited by muscarinic receptor occupation are inhibition of adenylyl cyclase, stimulation of phos-phoinositide hydrolysis and regulation of potassium or other ion channels [47] (Fig. 11-10). The particular receptor subtypes eliciting those responses are discussed below. (See also Chs 20 and 21.)... 

A third group of MAPKs are p38 kinases, of which there are four subtypes a, [3, y, and 8. P38 MAPKs are activated by many stimuli including hormones, ligands for G-protein-coupled receptors and stresses [13,17]. P38 MAPK has been implicated in the pathological changes accompanying inflammatory and apoptotic processes of various cell types, including neurons [17] (see Ch. 35 for... 

When epinephrine occupies its receptor it activates the ligand binding/ G-protein/ adenylate cyclase cascade. This in turn phosphorylates the muscle enzyme, phosphorylase. This form of the enzyme is the active form which cleaves glucose 1-phosphate unit from glycogen, eventually depleting it... 

An extended (seven-sided) ternary complex model (Fig. 2B) was proposed by Samama et al. (1993) to accommodate mutant receptors that exhibited constitutive activity and to link receptor affinity with efficacy. This model includes the isomerization of the receptor between two conformational states, inactive (R) and active (R ), and only allows for the active R conformational state to interact with the G protein. Conceptually, the model allows for the receptor to toggle between on and off states where ligand or G protein manipulates the population size of these two conformational states, rather than affecting the activation strength of a particular conformational state. The different types of ligands influence... 

GPCR interactions with ligand and G protein are represented by the ternary complex formalism (Fig. 2A Christopoulos and Kenakin, 2002 De Lean et al, 1980 Sam am a et al, 1993). The quantitative analysis of the soluble assembly system formally requires inclusion of soluble G protein due to the use of a crude receptor preparation. These soluble G proteins compete with the G protein attached to the G-beads for the solubilized receptor as shown in Fig. 2C (Simons et al, 2003, 2004). Experimental values from G-beads (Fig. 3) were fitted with the calculations of bead-bound receptors (RG k..i< + ARG k. i< ) based on this model, which includes soluble G proteins. Simulations were made by Mathematica , numerically solving the series of... 

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