7-helix transmembrane receptors

Fig. 5.2. Structural principles of transmembrane receptors, a) Representation of the most important functional domains of transmembrane receptors, b) Examples of subunit structures. Transmembrane receptors can exist in a monomeric form (1), dimeric form (2) and as higher oligomers (3,4). Further subunits may associate at the extracellular and cytosohc domains, via disulfide bridges (3) or via non-covalent interactions (4). c) Examples of structures of the transmembrane domains of receptors. The transmembrane domain may be composed of an a-hehx (1) or several a-helices linked by loops at the cytosolic and extracellular side (2). The 7-helix transmembrane receptors are a frequently occurring receptor type (see 5.3). Several subunits of a transmembrane protein may associate into an ohgomeric structure (3), as is the case for voltage-controUed ion channels (e.g., K channel) or for receptors with intrinsic ion channel function (see Chapter 17).

Due to the common appearance of 7 transmembrane helices, the family of G-protein coupled receptors is also known as the family of the 7-helix transmembrane receptors. The G-protein coupled receptors are also sometimes called the serpentine receptors, pointing to the serpentine-like configuration of transmembrane hehces. 

The heterotrimeric G-proteins are the specific reaction partners in signal transmission via 7-helix transmembrane receptors, which is why these receptors are also known as G-protein-coupled receptors. From the G-protein, the signal is then passed on to the effector protein next in the sequence (review Hepler and Gilman, 1992 Neer, 1995). 

The 7-helix transmembrane receptors are often glycoproteins. Glycosylation sites are located in the extracellular region, e.g., in the form of the consensus sequence Asn-X-Ser/Thr for an N-linked glycosylation. 

Phosphorylation of the cytoplasmic domain of 7-helix transmembrane receptors can take place via cAMP-dependent protein kinases protein kinase A) or via protein kinase C (Chapter 7) (Fig. 5.9). This is a feedback mechanism. The hormonal activation of the receptor leads, via G proteins and adenylyl cyclase/cAMP, to activation of protein kinases of type A (see Sections 5.6.1 and 6.1, and Chapter 7). The activated protein kinases phosphorylate the receptor in the region of the cytoplasmic domain on Ser/Thr residues. Regulation via adenylyl cyclase/cAMP/proteinkinase A is an example of a heterologous desensitization, since adenylyl cyclase can be activated by a variety of signals originating from different signaling pathways (see Section 5.6.1). 

The major mechanism for the homologous desensitization of agonist-bound 7-helix transmembrane receptors consists of a two-step process in which the agonist-bound receptor is phosphorylated by a GRK and then binds an arrestin protein which interrupts signaling to the G protein. Well-characterized GRKs (review Pitcher et al., 1998) are those for rhodopsin, rhodopsin kinase and the fil adrenaline receptor, the -adrenergic receptor kinase (/ ARK).The GRKs are protein kinases thatare... 

In another reaction, Ser/Thr phosphorylation of 7-helix transmembrane receptors can be used as a switch for coupling a given receptor to different Ga subunits, the downstream effector protein. Protein kinase A-mediated phosphorylation of the -adrenergic receptor has been shown to switch coupling of the receptor from Gs to Gj and trigger a new set of downstream signaling reactions (Daaka et al., 1997). 

Receptors and their ligands are numerous, varied, and essential to all forms of life. Cell-surface receptors on bacteria detect feeding attractants as well as dangerous molecules. From bacteria to humans seven-helix receptors function to detect light, odors, hormones, and other molecules. Tire numbers of different receptors are impressive. For example, the tiny nematode C. elegans has 650 seven-helix transmembrane receptors and 411 protein kinases, many of which may be associated with receptors.34 Our bodies have thousands. 

Herzyk, P., Hubbard, R. E. Automated method for modelling seven-helix transmembrane receptors from experimental data. Biophys. J., 1995, 69, 2419-2442. 

Levels of / -catenin are high when the Wnt ligand is available for binding to its receptor, which belongs to the class of seven-helix transmembrane receptors. The... 

Gautier A, Mott HR, Bostock MJ et al (2010) Structure determination of the seven-helix transmembrane receptor sensory rhodopsin II by solution NMR spectroscopy. Nat Struct Mol Biol 17 768-774... 

Human CBi is present in the brain and throughout the central nervous system and has 472 amino acids CB2 is present in the spleen and the immune cells and has 360 amino acids. Both types are 7-helix transmembrane spanning receptors. There are three extra cellular and three intra cellular loops. A glycosylated extra cellular N-terminal domain, and an intra cellular C-terminal domain are involved in the interaction with the G-protein. 

The currently accepted structural models of the G-protein coupled receptor tend strongly towards the well established structure of bacteriorhodopsin (Fig. 5.4) that is also a 7-helix transmembrane protein. The model assumes that the seven helices are bedded bimdle-wise in the membrane. Detailed structural information on the conformation of the extracellular and intracellular structural portions is still lacking. 

Many other receptors are 7-helix transmembrane proteins, which activate guanine nucleotide G proteins (Chapter 11, Section D, 3). The G proteins couple some receptors directly to Ca2+ channels they couple other receptors to adenylate cyclase and cyclic AMP-activated channels and yet others via phospholipase C to K+ channels and indirectly to Ca2+ channels (Fig. 30-19). All of these G protein coupled receptors are referred to as metabotropic receptors. A single synapse often contains both ionotropic receptors and metabotropic receptors. The ionotropic receptors induce a rapid (< 1 ms) response, while the metabotropic receptors act more slowly. However, in most cases the final effect is the release of calcium ions into the cytoplasm... 

Single transmembrane helix Ca2+ receptor N terminus in vesicle SNARE proteins, C termini in vesicle Integral membrane protein Integral membrane protein, Cl- transporter Integral membrane protein Integral membrane protein 13 subunits H+ generator... 

Both adrenaline and noradrenaline stimulate smooth muscles throughout the body and have a hypertensive effect. Their postsynaptic receptors are 7-helix transmembrane proteins (Fig. 11-6). A comparison of the effects of various analogs led to the classification of these receptors into classes a, a2, P, and P2, which are discussed briefly on pp. 553-555. The a receptors, which are structurally closely related to rhodopsin,753/754 are coupled via Gq /11 proteins to a phosphoinositide-activated phospholipase C (Figs. 11-9, 30-19).755 They usually provoke an excitatory response. However, in intestinal smooth muscles they are inhibitory. Adrenaline is usually more active at a receptors than is noradrenaline. A specific antagonist... 

Cytokines all function using a group of transmembrane receptors embedded in the plasma membranes of target cells. The receptors have no tyrosine kinase activity but associate with and activate kinases known as Janus kinases (JAKs). These kinases phosphory-late tyrosine side chains in their receptors, and the phosphorylated receptors activate transcription factors of the STAT (signal transducer-activators of transcription) group.186-195 The specificity of cytokine action results from a combination of receptor recognition and recognition of the various STAT molecules by different JAKs.111 Cytokines have a variety of structures. Many are helix bundles or have (3 sheet structures (Fig. 30-6). 

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