G-protein linked receptor

Birdsall NJ, Cohen F, Lazareno S, Matsui H. Allosteric regulation of G-protein-linked receptors. Biochem Soc Trans 1995 23 108-111. 

The finding that extracellular loop 2 of the k receptor is a ligand binding domain is not unique among G protein-linked receptors. Recent mutagenesis stud-... 

Sinkins, W. G., Kandel, M Kandel, S. I., Schunack, W and Wells, J. W. (1993) G protein-linked receptors labeled by [3H]histamine in guinea pig cerebral cortex. I. Pharmacological characterization [corrected]. Mol. Pharmacol. 43, 583-594. 

Maggio, R., Vogel, Z., and Wess, J. (1993) Coexpression studies with mutant muscarinic/adrenergic receptors provide evidence for intermolecular cross-talk between G protein-linked receptors. Proc. Natl. Acad. Sci. USA 90, 3103-3107. 

Maggio, R., Barbier, P., Colelli, A., Salvadori, F., Demontis, G., and Corsini, G. U. (1999) G protein-linked receptors pharmacological evidence for the formation of heterodimers. J. 

Figure 3.2. Structure of some G-protein-linked receptors of the rhodopsin superfamily (a) the structural organisation of the predicted hydrophilic and hydrophobic domains of the receptor (b) how the hydrophilic regions form extracellular and intracellular loops, being anchored by the seven hydrophobic transmembrane domains.

Activation of neutrophils with PAF occurs through a G-protein-linked receptor, and the subsequent transmembrane signalling involves the stimulation of inositol phosphate metabolism. Within 30 s of addition of PAF (0.01-100 nM), intracellular Ca2+ levels increase and Ca2+ transport from the external medium is enhanced. It seems that phospholipase C-dependent and -independent activation pathways are involved in Ca2+ mobilisation. This indirectly suggests that two receptors may be involved in PAF activation. The first of these is pertussis-toxin-insensitive and may be linked to a... 

An alternative approach to clone the receptor was taken by Thomas and colleagues (1990, 1991). They screened a cDNA library from peritoneal rabbit cells with an antisense oligonucleotide probe deduced from the coding region of the second transmembrane domain, which is common to G-protein-coupled receptors (fMet-Leu-Phe is a G-protein-linked receptor). Screening of this library yielded a putative receptor clone F3R, characterised as follows ... 

This clone, however, had only 56% homology at the amino acid level to the clone described by Boulay et al., and it has since been shown actually to encode the IL-8 receptor, which is also a G-protein-linked receptor with seven transmembrane loops (see Fig. 3.2). 

The receptors for fMet-Leu-Phe, C5a and PAF have all been cloned (see Chapter 3) and possess the predicted seven membrane-spanning domains present in other G-protein-linked receptors of the rhodopsin superfamily (see Fig. 3.2). The pertussis-toxin sensitivity of the G-proteins associated with these receptors arises from the ADP-ribosylation of a cysteine residue that is four amino acids from the COOH-terminus of the molecule. Some other pertussis-toxin-insensitive G-proteins that exist lack this critical cysteine residue. 

Anti-diuretic hormone is a small peptide shown as Figure 8.9, which is secreted by the pituitary gland located at the base of the brain. The cellular actions of ADH are mediated by activation of a G-protein linked receptor generating cAMP as second messenger. Absence of ADH or a functional defect in the action of ADH-stimulated water reabsorption in the collecting duct results in the condition diabetes insipidus, characterized by the passing of large volumes (= diabetes) of dilute (= insipidus) urine. 

Witherup KM, Ransom RW, Graham AC, Bernard AM, Salvatore MJ, Lumma WC, Anderson PS, Pitzenberger SM, Varga SL (1995) Martinelline and martinellic acid, novel G-protein linked receptor antagonists from the tropical plant Martinella iquitosensis (Bignoniaceae). J Am Chem Soc 117 6682-6685... 

Metabotropic G-protein linked receptors are also modulated by general anesthetics. In particular, the current produced through activation of muscarinic receptors (Ml) for acetylcholine and the serotonergic receptor 5HT2 is inhibited by halothane, isoflurane and enflurane (Lin et al., 1993 Minami et al., 1994 Durieux, 1995). Ketamine inhibits muscarinic receptors although there is no stereospecificity of inhibition (Durieux Nietgen, 1997). The S-isomer of ketamine is more potent as an anesthetic than the R-isomer (Benthuysen et al., 1989). It is thus unlikely that the Ml muscarinic receptor plays a role in... 

Benzodiazepines facilitate inhibition by y-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. The benzodiazepine receptor is a subtype of the GABA receptor. Activation of the benzodiazepine receptor facilitates the action of endogenous GABA, which results in the opening of chloride ion channels and a decrease in neuronal excitability. Benzodiazepines act rapidly because ion channels can open and close relatively quickly, in contrast to the slower onset of action that occurs with G protein-linked receptors. 

Angiotensin II has a variety of effects. By constricting blood vessels it raises blood pressure, and by stimulating thirst centers in the brain it increases blood volume. Both angiotensins II and III also act on the adrenal gland to promote the synthesis and release of aldosterone. Most of the effects of angiotension II are mediated by 359-residue seven-helix G-protein linked receptors which activate phospholipase C.p q qr Like other steroid hormones aldosterone acts,via mineralocorticoid receptors, to control transcription of a certain set of proteins. The end effect is to increase the transport of Na+ across the renal tubules and back into the blood. Thus, aldosterone acts to decrease the loss of Na+ from the body. It promotes retention of water and raises... 

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