Heptahelical G-protein-coupled receptor

Opioids act on heptahelical G-protein-coupled receptors. Three types of opioid receptors (p, 8, k) have been cloned. Additional subtypes (e.g., pl3 p2, 81 82), possibly resulting from gene polymorphisms, splice variants or alternative processing have been proposed. Opioid receptors are localized and can be activated... 

Somatostatin acts on various organs, tissues and cells as neurotransmitter, paracrine/autocrine and endocrine regulator on cell secretion, smooth muscle contractility, nutrient absorption, cell growth and neurotransmission [1]. Some of its mainly inhibitory effects are listed in Table 1. Somatostatin mediates its function via a family of heptahelical G-protein-coupled receptors termed... 

The majority of the 5-HT receptor subtypes am heptahelical G protein-coupled receptors (GPCRs) with the noted exception of 5-HT3 receptors, which form ligand-gated ion channels (6,7). Thus, GPCR-interacting proteins, either soluble or transmembrane, stood out as some of the best characterized FRAPs. Together, 5-HT receptors and their FRAPs constitute a structural and functional network of proteins known as the receptosome (8). 

The insulin receptor will be discussed here as a prototype of a receptor with tyrosine kinase activity which transmits a hormonal signal. The other major classes of receptors which transmit hormonal signals are the heptahelical, G-protein-coupled receptors and the nuclear receptors for steroid and non-steroid hormones (see Fig. 1.1) they are discussed later. The receptor for the peptide hormone insulin is one of the most extensively studied RTKs (receptors with tyrosine kinase activity). 

Signalling is initiated by binding of Wnt-factors to the Wnt or Frizzled receptors. These receptors resemble remotely heptahelical, G-protein-coupled receptors (Chapter... 

The visual transduction pathway is the best characterized G-protein-coupled signal transduction system. Study of the visual receptor, rhodopsin, over the past several decades has made it the archetype of the growing superfamily of heptahelical G-protein-coupled receptors (reviewed in Litman Mitchell, 1996a). The preeminent position of rhodopsin in this important superfamily will likely increase with the recent publication of the three-dimensional structure of rhodopsin (Palczewski et al., 2000). Many neurotransmitter receptors, as well as the olfactory and taste receptors, are members of this superfamily. Therefore, the effect of lipid membrane composition on various steps in visual signaling will be reviewed in some detail in this chapter. Given the similarity in mode of signaling, the observations made for the vision system should be of general applicability to other members of this receptor superfamily. 

It has been reported that serotonin can produce opposite and complementary action on neuronal functioning, maturation, proliferation and apoptosis, depending on the kind and the density of receptors synthesized by the cells [1]. There are at least fourteen different receptor subtypes described for 5-HT, 13 different heptahelical G-protein-coupled receptors and one ligand-gated ion channel (Table 3). The 5-HT receptor family has been, and is at present, subjected to intense research. Excellent and complete reviews of functional, molecular and pharmacological aspects of 5-HT receptors have been published [5-7]. 

Heptahelical receptors, another name for 7 TM receptors or G-protein-coupled receptors. It refers to the motif of the helices of the protein crossing the cell membrane seven times to form intracellular and extracellular domains. 

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... 

Fig. 6.1 Schematic representation of the cysteinyl leukotriene 2 (CysLT ) receptor. Ribbon model of this family A G protein-coupled receptor (GPCR) is pictured in its heptahelical configuration. The extracellular amino terminus of the receptor, the transmembrane domains, and the intracellular carboxyl tail extend behind the intracellular palmitoylation site. The putative binding pocket for cysteinyl leukotriene ligands is derived from a rhodopsin model...

The P2 receptor nomenclature was prompted by evidence that extracellular ATP works through two different transduction mechanisms, namely intrinsic ion channels and G-protein coupled receptors (Benham and Tsien, 1987 Dubyak, 1991). In 1994 it was formally suggested that P2 receptors should be divided into two groups termed P2X and P2Y according to whether they are ligand-gated ion channels (Fig. 1) or are coupled to G-proteins - metabotropic receptors belonging to the heptahelical superfamily (Abbracchio and Burnstock, 1994 Barnard et al., 1994 Fredholm etal., 1994). 

GPCRs are heptahelical, serpentine receptors, which pass the membrane seven times. They have no kinase activity. Prototype G-protein-coupled receptors are the (3-adrenergic receptors, which transmit the signals of the hormone adrenaline (epinephrine) and rhodopsin (which transmits the light signal in the rod outer segment membrane and initiates the visual response in the eye). More than 40 sequences alone for the (3-adrenergic receptors have been derived from cDNAs. ... 

Only recently was the first higfr-resolution atomic structure of a G-protein-coupled receptor solved, namely that of rhodopsin, although lower-resolution spatial structural information based on two-dimensional crystals and electron diffraction and NMR structures was available.3.4 This information makes it certain that all heptahelical receptors have the same topological arrangement of the polypeptide chains. The amino- and carboxy-termini are oriented in the same way, with the amino-terminus outside and carboxy-terminus on the cytoplasmic side. Valuable structural relationships between different G-protein-coupled receptors for hormones have also come to light, mainly thanks to comparisons of cDNA-derived sequences. ... 

It has been known for quite some time that signalling pathways controlled by growth factors and cytokines accept signals from heptahelical receptors, coupled to heterotrimeric G proteins. However, the individual steps that funnel hormonal signals via G-protein-coupled receptors and heterotrimeric G proteins into the Ras/MAP kinase pathway were not well defined. This state of affairs has changed recently. We now have an idea, although not yet complete, how hormones may contribute to the regulation of cell proliferation via G-protein-coupled receptors. 

Both in the case of sensory rhodopsin in humans and of bacteriorhodopsin (a heptahelical membrane protein in halobacteria which is not coupled to a G protein) translocation of a Schiff-base proton is the essential step in making the protein functional (reviewed in ref 58). In rhodopsin the conversion of the inactive AH state to the AHI state that binds to the G protein is coupled to proton transfer from the Schiff base to the counterion, Glul 13, and proton uptake from the medium to the highly conserved Glul34, which serves as proton acceptor. Based on that similarity, one could consider sensory rhodopsin as an incomplete proton pump. Furthermore, a property shared by all G-protein-coupled receptors is a triplet, formed by residues 134-136 in rhodopsin, consisting of Glu-Arg-Tyr. The consequences of mutational replacement of Glul34 supports the notion that the state of protonation of this amino add is crudal for activity, and that its protonation triggers the conformational transition of the receptor from the inactive to the active state. 

G protein-coupled receptors are a large class of transmembrane receptors. They have seven transmembrane helices. Therefore, they are called heptahelical or serpentine receptors. They bind watersoluble hormones, such as adrenaline but also peptides and accept sensory signals, light, odorants and some taste stimuli. On binding the ligand they transmit the signal to heterotrimeric, a,p,y-G proteins. 

Landry, Y., Niederhoffer, N., Sick, E., Gies, J.-P. Heptahelical and other G-protein-coupled receptors (GPCRs) signalling. Curr. Med. Chem. 2006, 13, 51-63. 

Receptors are divided into five major classes (Table 10.1) the heptahelical, 7-transmem-brane (7-TM) G-protein-coupled receptor (GPCR) class, the ion channel class, the steroid receptor superfamily, intracellular receptors, and the non-GPCR-linked cytokine receptors. Of these, the 7-TM receptors have historically represented the most fertile class for drug discovery (2), perhaps primarily because they have been the most studied. Ion channels can be further subdivided into li-... 

Heterotrimeric G-proteins are guanine nucleotide-binding membrane-associated proteins that directly intermediate between the G-protein-coupled (heptahelical) receptor and the target effector protein. They are composed of a, P and y subunits. The trimer is anchored in the membrane via palmitoyl or myristoyl fatty acids at the N-terminus of the a subunit and a prenyl moiety at the C-terminus of the y-subunit (see Gilman 1987 Oldham and Hamm 2006 for details). 

The G-protein-coupled heptahelical receptors are the largest transmembrane receptor class. They may take up 2% of the genome. Altogether, there may be thousands of different receptor molecules of this type that all transmit their signals through a heterotrimeric GTP-binding protein. These receptors are dealt with in Chapter 5. 

The first step in the activation of G proteins is the replacement of GDP by GTP. Whereas in the case of heterotrimeric G proteins, GDP-GTP exchange is catalysed by G-protein-coupled heptahelical receptors, monomeric G proteins, such as Ras, recruit GDP exchange factors (GEFs) and guanine nucleotide release proteins (GNRPs). These factors promote formation of the active, GTP-bound form of Ras and, because they are linkers, connect Ras with the RTK. 

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