Heptahelical Receptors

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. 

Seven transmembrane helix receptors Heptahelical receptors Serpentine receptors... 

GPCRs are proteins that span the postsynaptic cell membrane seven times (heptahelical receptors). Small ligands are usually bound within a pocket formed by the... 

Heparin Sulfate Proteoglycans Hepatic Lipase Hepatitis Hepatitis C Heptahelical Domain Heptahelical Receptors HERG-channels Heterologous Desensitization Heterologous Expression System Heterotrimeric G-Proteins Hidden Markov Model High-density Lipoprotein (HDL)... 

Perry SJ, Lefkowitz RJ. Arresting developments in heptahelical receptor signaling and regulation. Trends Cell Biol 2002 12(3) 130—138. 

Hall RA, Premont RT, Lefkowitz RJ. Heptahelical receptor signaling beyond the G protein paradigm. J Cell Biol 1999 145(5) 927—932. 

Lefkowitz, R. J. (2000) The superfamily of heptahelical receptors. Nature Cell Biology, 2, E133-E136. 

Agnati, L.F., Ferre, S., Lluis, C., Franco, R. and Fuxe, K. (2003) Molecular mechanisms and therapeutical implications of intramembrane receptor/receptor interactions among heptahelical receptors with examples from the striatopallidal GABA neurons. Pharmacological Reviews, 55, 509-550. 

Rebois, R. V., and Hebert, T. E. (2003) Protein complexes involved in heptahelical receptor-mediated signal transduction. Receptors Channels. 9, 169-194. 

A great deal of structural information about G proteins is known from x-ray crystallographic studies, providing insight into GTP-mediated conformational changes in Ga, subunit interactions with effector proteins, and the mechanism of GTP hydrolysis. By contrast, relatively little structural information is known about the interaction between the receptor and G protein and how this interaction leads to GDP release. After an overview of the structure of heptahelical receptors and heterotrimeric G proteins, this chapter will discuss the current models of the receptor-G protein complex and proposed mechanisms for receptor-catalyzed nucleotide exchange. 

Fig. 2. Structure of a heptahelical receptor. Cartoon model of dark (inactive) bovine rhodopsin (1U19), showing the seven transmembrane-spanning a helices (red to blue) and 11-r/Vi ctinal (gray spheres). Conserved residues important for receptor and G protein activation are shown (magenta spheres), including the DRY motif on helix III (yellow) and NpxxYx5F motif on helices VII and VIII blue and purple). The extracellular and intracellular faces of rhodopsin are shown. Receptor activation results in an outward movement of helix VI yellow arrow), which opens a gap in the cytoplasmic face of the receptor, exposing residues critical for G protein activation, such as the DRY motif on helix III (yellow).

Although nearly 900 different heptahelical receptors have been identified in the human genome (Fredriksson and Schioth, 2005), they activate relatively few types of G proteins, composed of a, j>. and y subunits. At last count, there are 21 Ga subunits encoded by 16 genes, 6 G/l subunits encoded by 5 genes, and 12 Gy subunits (Downes and Gautam, 1999). The heterotrimeric G proteins are typically classified into four families based on the primary sequence similarity of the Ga subunit Gas, Ga,. Gaq,... 

LPH is a large (185 kDa) heptahelical receptor. It comprises three major domains (Figure 4a) (1) a long, glycosylated N-terminal extracellular domain (2) seven hydrophobic TMRs and (3) a long cytoplasmic tail. The ectodomain contains... 

Hayflick JS (2000) A family of heptahelical receptors with adhesion-like domains a marriage between two super families. J Recept Signal Transduct Res 20 119-31 Hlubek M, Tian D, Stuenkel EL (2003) Mechanism of a-latrotoxin action at nerve endings of neurohypophysis. Brain Res 992 30-42... 

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). 

Hahn A, Heusinger-Ribeiro J, Lanz T, Zenkel S, Goppelt-Struebe M. Induction of connective tissue growth factor by activation of heptahelical receptors. Modulation by Rho proteins and the actin cytoskeleton. J Biol Chem 2000 275 ... 

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. 

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. ... 

A critical analysis of the on and off rates of ligand-receptor interactions made it clear that deactivation of a heptahelical receptor can not be determined by the decay of the... 

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