Seven transmembrane domains

Foord, S. M., and Marshall, F. H. (1999). RAMPS Accessory proteins for seven transmembrane domain receptors. Trends Pharmacol. Sci. 20 184-187. 

Somatostatin is a regulatory cyclic peptide, which has originally been described as a hypothalamic growth hormone release-inhibiting factor. It is produced throughout the central nervous system (CNS) as well as in secretoty cells of the periphery and mediates its regulatory functions on cellular processes such as neurotransmission, smooth muscle contraction, secretion and cell proliferation via a family of seven transmembrane domain G-protein-coupled receptors termed sstx 5. 

Figure 6.4 Schematic representation of the muscarinic receptor. All muscarinic receptors have seven transmembrane domains and the major difference between them is within the long cytoplasmic linkage connecting the fifth and sixth domains. This implies different G-protein connections and functions. Some possibilities are shown although the position of the Mi and M2 boxes is not intended to indicate their precise structural differences within the loop...

The precise role of melatonin in sleep and waking is uncertain but it seems to act as a go-between for the light and biological cycles and evidence suggests that it has a reciprocal relationship with the SCN (Fig. 22.3). Its actions are mediated by (MLi) receptors which are found predominantly in the SCN as well as thalamic nuclei and the anterior pituitary. These are G protein-coupled receptors, with seven transmembrane domains, that inhibit adenylyl cyclase. Their activation by melatonin, or an MLi agonist such as 2-iodomelatonin, restores the impaired circadian cycle in aged rats. 

Chemokines are a superfamily of low-molecular-weight chemotactic cytokines that exert their effects through seven transmembrane domain G protein-coupled receptors. Although some chemokines are constitutively expressed in certain settings, most are induced by proinflammatory mediators, such as IFN-y and TNF-a. Upon binding to the appropriate receptor, chemokines initiate a... 

Most neuropeptide receptors are seven-transmembrane-domain, G-protein-coupled receptors 326 Neuropeptide receptors are not confined to synaptic regions 327 Expressions of peptide receptors and the corresponding peptides are not well matched 327... 

FIGURE 18-10 Serpentine (seven-transmembrane-domain) receptors for peptides have binding for their peptide ligands within the membrane... 

G-Protein coupled receptors (GPCR) represent the start element in secondary messenger producing systems. They comprise a family of over 1000 structurally-related members. These membrane proteins are also called serpentine or seven-helix receptors due to their seven transmembrane domains with an a-helical conformation. Receptors belonging to this class respond to a variety of hormones and neurotransmitters, and they detect odorant molecules or light [3,4]. 

Hu, J., Reyes-Cruz, G., Chen, W., Jacobson, K. A., and Spiegel, A. M. (2002) Identification of acidic residues in the extracellular loops of the seven-transmembrane domain of the human Ca2+ receptor critical for response to Ca2+ and a positive allosteric modulator. J. Biol. Chem. 277,46622-46631. 

Although varying considerably in molecular size, any GPCR polypeptide sequence contains seven hydrophobic a-helices that span the lipid bilayer and dictate the typical macromolecule architecture. Seven transmembrane domains bundled up to form a polar internal tunnel and expose the N-terminus and three interconnecting loops, to the exterior, and the C-terminus with a matching number of loops, to the interior of the cell [1-3]. This structural information was recently confirmed by the resolution of the crystal structure of rhodopsin [4,5]. 

Metabotropic receptors, in contrast, create their effects by activating an intracellular G protein. The metabotropic receptors are monomers with seven transmembrane domains. The activated G protein, in turn, may activate an ion channel from an intracellular site. Alternately, G proteins work by activation or inhibition of enzymes that produce intracellular messengers. For example, activation of adenylate cyclase increases production of cyclic adenosine monophosphate (cAMP). Other effector mechanisms include activation of phospholipases, diacylglycerol, creation of inositol phosphates, and production of arachidonic acid products. Ultimately, these cascades can result in protein phosphorylation. 

The superfamily of seven-transmembrane-domain G-protein-coupled receptors is a diverse group of transmembrane proteins involved in signal transduction [1, 2]. GPCRs are of extraordinary importance for the pharmaceutical industry in that space nearly 40% of marketed drugs act through modulahon of the GPGR functions [3]. 

All muscarinic receptors are members of the seven transmembrane domain, G protein-coupled receptors, and they are structurally and functionally unrelated to nicotinic ACh receptors. Activation of muscarinic receptors by an agonist triggers the release of an intracellular G-protein complex that can specifically activate one or more signal transduction pathways. Fortunately, the cellular responses elicited by odd- versus even-numbered receptor subtypes can be conveniently distinguished. Activation of Ml, M3, and M5 receptors produces an inosine triphosphate (IP3) mediated release of intracellular calcium, the release of diacylglyc-erol (which can activate protein kinase C), and stimulation of adenylyl cyclase. These receptors are primarily responsible for activating calcium-dependent responses, such as secretion by glands and the contraction of smooth muscle. 

Five subtypes of dopamine receptors have been described they are the Dj-like and Dj-like receptor groups. All have seven transmembrane domains and are G protein-coupled. The Dj-receptor increases cyclic adenosine monophosphate (cAMP) formation by stimulation of dopamine-sensitive adenylyl cyclase it is located mainly in the putamen, nucleus accumbens, and olfactory tubercle. The other member of this family is the D5-receptor, which also increases cAMP but has a 10-fold greater affinity for dopamine and is found primarily in limbic regions. The therapeutic potency of antipsychotic drugs does not correlate with their affinity for binding to the Dj-receptor. 

The prostanoid receptors are G-protein coupled rhodopsin-type receptors with seven transmembrane domains [6] (Fig. 3). The overall homology among the receptors is not high, though these receptors conserve the important amino acid sequences in several regions, especially in the seventh transmembrane domain. 

Cao, J., Panetta, R., Yue, S., Steyaert, A., Young-BelKdo, M. and Ahmad, S. (2003) A naive Bayes model to predict coupling between seven transmembrane domain receptors and G-proteins. Bioinformatics 19, 234-240. 

Figure 4.3 Schematic representation of a 7-transmembrane receptor, exemplified with the human neurokinin-1 receptor (hNK,) The extracellular elements of the receptor are shown in the upper part the amino-acid chain ends with a free amino-residue (NH2) and is called the amino-terminal of the receptor. The longer amino acid chain of the intracellular part (lower part) ends with a free acid-residue (COOH) and is called the carboxylic end. The seven transmembrane domains are lined up within the box, which represents the membrane...

Endothelin receptors are widespread in the body. Two endothelin receptor subtypes, termed ET and ET , have been cloned and sequenced. receptors have a high affinity for ET-1 and a low affinity for ET-3 and are located on smooth muscle cells, where they mediate vasoconstriction (Figure 17-7). ETB receptors have approximately equal affinities for ET-1 and ET-3 and are primarily located on vascular endothelial cells, where they mediate release of PGI2 and nitric oxide. Some ETB receptors are also present on smooth muscle cells and mediate vasoconstriction. Both receptor subtypes belong to the G protein-coupled seven-transmembrane domain family of receptors. 

Three subtypes of NT receptors, designated NT 1, NT 2, and NT 3, have been cloned. NT and NT2 receptors belong to the G protein-coupled superfamily with seven transmembrane domains the NT3 receptor is a single transmembrane domain protein that belongs to a family of sorting proteins. 

Chemokine receptors are a family of G protein-coupled receptors that contain seven transmembrane domains. Chemokine receptors are present on the cell surface membrane of leukocytes. As was the case for chemokines, these receptors are also divided into four subgroups CCR is specific for CC chemokines, CXCR for CXC chemokines, XCR1 for C chemokines and CX3CR1 for CX3C chemokines. The CC chemokine receptor family has eleven members, the CXC chemokine receptor family has seven members, and both the C chemokine receptor family and the CX3C chemokine receptor family have one member each. The signal transduction is mediated via the standard G protein-dependent pathway. 

Ho, C, Conner, DA, Poliak, MR, Ladd, DJ, Kifor, O, Warren, HB, Brown, EM, Seidman, JG and Seidman, CE, 1995, A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism [see comments], Nat Genet 11 389-394 Hu, J, McLarnon, SJ, Mora, S, Jiang, J, Thomas, C, Jacobson, KA and Spiegel, AM, 2005, A region in the seven-transmembrane domain of the human Ca21 receptor critical for response to Ccp-+, J Biol Chem 280 5113-5120... 

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