Loops intracellular

Fig. 5. Schematic diagram of the presumed arrangement of the amino acid sequence for the 5-opioid receptor, showing seven putative transmembrane segments three intracellular loops, A three extracellular loops, B the extracellular N-terrninus and the intracellular C-terrninus, where (0) represents amino acid residues common to ] -, 5-, and K-receptors ( ), amino acid residues common to all three opioid receptors and other neuropeptide receptors and (O), other amino acids. Branches on the N-terruinal region indicate possible glycosylation sites, whereas P symbols in the C-terminal region indicate...

Fig. 12. Model for the P-adenergic receptor. It is proposed that the receptor possesses seven hydrophobic heUces that span the plasma membrane and are connected by alternating extracellular and intracellular loops (79). The site of glycosylation is represented as CHO. Reprinted with permission from Elsevier...

Heptahelical domains are protein modules found in all known G-protein coupled receptors, made up of seven transmembrane helices interconnected by three extra and three intracellular loops. For most G-protein coupled receptors activated by small ligands, the binding site is located in a cavity formed by transmembrane domains 3, 5, 6 and 7. 

Alike any other G-protein coupled receptors (GPCRs), mGlu receptors have seven transmembrane helices, also known as the heptahelical domain (Fig. 2). As observed for all GPCRs, the intracellular loops 2 and 3 as well as the C-terminal tail are the key determinants for the interaction with and activation of G-proteins. However, sequence similarity analysis as well as specific structural features make these mGlu receptors different from many other... 

The structure of all TK receptors is similar in terms of expression oiTACR genes, since all these genes contain five exons intercalated by four introns [1, 5]. Exon I encodes for the N-terminal extracellular tail, the first intracellular (IC1) and extracellular (EC1) loops and the first, second, and third transmembrane domains (TM1, TM2, and TM3). Exon II encodes for the second intracellular (IC2) and extracellular (EC2) loops and the fourth transmembrane domain (TM4). Exon III encodes for the fifth transmembrane domain (TM5) and the third intracellular loop (IC3). Exon IV encodes for the sixth and seventh transmembrane domains (TM6 and TM7) and the third extracellular loop. Exon V encodes for the C-terminal intracellular tail only. A schematic drawing of the amino acid sequences and TK receptor organization is shown in Fig. 1. 

Many GPCRs contain one or more conserved cysteine residues within their C-terminal tails, which are modified by covalent attachment of palmitoyl or isoprenyl residues. The palmitoyl moiety is anchored in the lipid bilayer forming a fourth intracellular loop. There is evidence that palmitoylation of a GPCR is a dynamic process and may affect receptor desensitization. 

G-protein-binding domain on the third intracellular loop... 

Figure 3.4 Transmembrane topology of a 7-TM domain G-protein receptor such as the P-adrenoceptor. Agonist binding is predicted to be within the transmembrane domains. The extracellular structure is stabilised by the disulphide bond joining the first and second extracellular loop. The third intracellular loop is the main site of G-protein interaction while the third intracellular loop and carboxy tail are targets for phosphorylation by kinases responsible for initiating receptor desensitisation...

All rhodopsin-like G-protein-coupled receptors have a conserved arginine residue at the intracellular end of TM3 and this residue is thought to be crucial for G-protein activation. The third intracellular loop determines the class of G-protein activated by the receptor with the second intracellular loop and C-terminus also influencing G-protein binding in some cases. Four classes of G-protein are known ... 

Using chimaeric receptors it has been shown that swapping the third intracellular loop between receptors also swaps their G-protein selectivity. The G-protein-binding... 

By far the most studied family of the G-protein-coupled receptors are the rhodopsin-like receptors. These are also the largest group of receptors in number as they include receptors not only for the monoamines, nucleotides, neuropeptides and peptide hormones, but they also include the odorant receptors which number several hundreds of related receptors. These receptors have short N-termini, a conserved disulphide bridge between the TM2-TM3 and TM4—TM5 extracellular domains, and variable-length C-termini. In some cases the C-terminus is myristolyated which by tying the C-terminus to the cell membrane generates a fourth intracellular loop. 

Figure 7.4 Comparative schematic representation of the Dj ( ) and D (—) dopamine receptor. The figure attempts to highlight the major differences between extra- and intracellular loops, especially the intracellular loops between transmembrane sections 5 and 6 and the much longer C terminal of the Dj compared with the D2 receptor. It is based on the proposed topography of Sibley and Monsma (1992). The thickened length of the D2 receptor represents the amino-acid sequence missing in the short form of the receptor. No attempt has been made to show differences in amino-acid sequencing or transmembrane topography...

Figure 11.7 Presumed arrangement of GABAa receptor subunits to form a receptor-channel complex, (a) Diagrammatic representation of an individual subunit with four transmembrane regions, extracellular sites for glycosylation and a site for phosphorylation on the intracellular loop between M3 and M4. (b) Association of five subunits to form a central ionophore bounded by the M2 region of each subunit. The suggested stoichiometry of the most widely expressed form of receptor is 2a, 2 and ly. Shown below are the possible subunit combinations of one such benzodiazepine-sensitive receptor together with a benzodiazepine-insensitive receptor in which the 7 subunit is replaced by a c5, and a ti-containing receptor with four different subunit types...

A further importance of cysteines lies in the palmitoylation of chemokine receptors. Many chemokine receptors have cysteine residues in their carboxy-terminal regions. In other GPCRs, these have been implicated in palmitoylation and in the anchoring of the carboxy-terminus to the plasma membrane. This effectively generates a fourth intracellular loop in the receptors. Studies on CCR5 have identified a three-cysteine cluster in the carboxy-terminus that is... 

Damaj BB, McColl SR, Neote K, et al. Identification of G-protein binding sites of the human interleukin-8 receptors by functional mapping of the intracellular loops. FASEB J 1996 10(12) 1426-1434. 

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