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PubMed2004

[History and the present of metabotropic GABAB receptor].

GABAB receptor is the main inhibitory metabotropic receptor in mammalian central nervous system. This receptor is a member of the Family 3 G-protein coupled receptors (GPCR). It is related to the metabotropic glutamate receptors, the calcium-sensing receptor and some vomeronasal receptors. The receptor is a heterodimer consisting of two subunits designated BR1 and BR2. Presynaptically. GABAB suppresses transmitter release via inhibition of Ca2+ channels, postsynaptically it increases K+ conductance resulting in hyperpolarization. The receptor is coupled to Gi/Go proteins and its activation can inhibit adenylyl cyclase activity. GABAs is widely distributed in CNS and peripheral tissues and plays an important role in many physiological and pathological processes. Recently, a novel GPCR with close relation to GABAB was cloned. It was termed GABABL, its role in GABAB activation has not been discovered yet.

Humans↗
PubMed2005

[The effects of anesthetics on G-protein-coupled receptors].

Although anesthetics have been often used clinically, the mechanisms of action of anesthetics have not yet been clarified. Recently, major advances have been made in our understanding of the physiology and pharmacology of G-protein-coupled receptor (GPCR)-mediated signaling. Several lines of studies have shown that GPCRs are targets for anesthetics and that some anesthetics inhibit the functions of Gq-coupled receptors, including muscarinic acetylcholine (ACh) M1, metabotropic type 5 glutamate, 5-hydroxytryptamine (5-HT) type 2 A, and substance P receptors. Many additional GPCRs have been classified as "orphan" receptors (oGPCRs) because their endogenous ligands have not been identified yet. Given that known GPCRs are targets for anesthetics, these oGPCRs may represent a rich group of receptor targets for anesthetics. This review highlights the effects of anesthetics on Gq-coupled receptors, and discusses whether GPCRs other than Gq-coupled receptors, and proteins that convey GPCR signals are also targets for anesthetics.

Anesthetics↗
PubMed2006

PAR-type thrombin receptors in renal carcinoma cells: PAR1-mediated EGFR activation promotes cell migration.

Cross-talk between G-protein-coupled receptor (GPCR) and epidermal growth factor receptor (EGFR) signaling systems is established in a wide variety of normal and neoplastic cell types. Here, we show that proteinase-activated receptor 1 (PAR1) mediates the tyrosine phosphorylation of EGFR in human renal carcinoma cells expressing PAR1 and PAR3 endogeneously. This GPCR-EGFR signal transduction pathway cross-talk requires matrix metalloproteinase activity and is involved in the regulation of renal carcinoma cell migration across a collagen barrier as shown using a Boyden chamber type assay. Our data therefore document a regulatory role of PAR1-mediated EGFR transactivation in cancer cell chemotactic migration. Further, our results underline the importance of PAR1-mediated pathways in kidney cancer cells and suggest that the thrombin/PAR1 system mediating EGFR transactivation may play a role in the progression of this tumor entity.

Cell Line, Tumor↗
PubMed1991

A novel membrane-bound serine esterase in human T4(+)-lymphocytes is a binding protein of envelope glycoprotein gp120 of HIV-1.

A novel membrane-bound serine esterase, named tryptase TL2, which is immunologically reactive with the antibody inhibiting induction of syncytia by human immunodeficiency virus-1 (HIV-1) (HATTORI, T., KOITO, A., TAKATSUKI, K., KIDO, H., and KATUNUMA, N., 1989, FEBS Lett., 248, 48-52), has been purified from a human T4+ lymphocyte clone. The enzyme has a molecular mass of 198 +/- 15 kDa, and is composed of two subunits of 32 kDa and four subunits of 28 kDa. The enzyme was strongly inhibited by the envelope glycoprotein gp120 of HIV-1, by synthetic peptides of V3 domains of gp120 s with the sequence GPGR in their center, which correspond to the principal neutralizing epitopes of the gp120s of various HIV-1 strains, by Kunitz-type inhibitors with the sequence GPCR in their active site, such as trypstatin, H130, and [Arg15, Glu52] aprotinin and by the microbial inhibitors leupeptin and antipain. This enzyme was specifically bound to the inhibitor V3 domain of gp120 of HIV-1, and this binding was blocked by the inhibitors of tryptase TL2, with a central motif GPCR or GPGR sequence in their center, but not by leupeptin and antipain without the motif. These findings suggest that tryptase TL2 is important in target site recognition and binding of HIV-1 in co-operation with CD4 receptor in the initial process of HIV-1 infection.

Alpha-Globulins↗
PubMed1994

A reciprocal mutation supports helix 2 and helix 7 proximity in the gonadotropin-releasing hormone receptor.

Activation of the pituitary gonadotropin-releasing hormone receptor, a member of the seven-transmembrane G protein-coupled receptor (GPCR) family, triggers a cascade of events leading to gonadotropin release and stimulation of the reproductive system. An unusual feature of this receptor, observed in mice, rats, and humans, is the presence of Asn87 in the second putative transmembrane helix at the location of a highly conserved aspartate in the GPCR family and of Asp318 in the putative seventh transmembrane helix where nearly all other GPCRs have asparagine. The possibility that these residues interact was suggested by this reciprocal pattern and by a three-dimensional model of the gonadotropin-releasing hormone receptor and was investigated by site-directed mutagenesis. Replacing Asn87 in the second transmembrane domain by aspartate eliminated detectable ligand binding. A second mutation, generating the double-mutant receptor Asp87Asn318, recreated the arrangement found in other GPCRs and re-established high affinity agonist and antagonist binding. The restoration of binding by a reciprocal mutation indicates that these two specific residues in helices 2 and 7 are adjacent in space and provides an empirical basis to refine the model of the transmembrane helix bundle of the receptor.

Amino Acid Sequence↗
PubMed1994

Hydrogen bonding interaction of thyrotropin-releasing hormone (TRH) with transmembrane tyrosine 106 of the TRH receptor.

Thyrotropin-releasing hormone (TRH, pyroglutamic acid-histidine-proline-amide) binds to a seven-transmembrane-spanning, G protein-coupled receptor. We tested the hypothesis that Tyr106 of the third transmembrane helix of the TRH receptor (TRH-R) binds pyroglutamyl of TRH by mutating Tyr106 to Phe and replacing the ring carbonyl of the TRH pyroglutamyl moiety with a methylene group ([Pro1]TRH). Compared to the affinity of wild-type TRH-R for TRH, the affinities of [Phe106]TRH-R for TRH and of wild-type TRH-R for [Pro1]TRH were 100,000- and 110,000-fold lower, respectively. The affinity of [Phe106]TRH-R for [Pro1]TRH was only 16-fold lower than that for TRH, demonstrating a lack of additivity of the effects of these changes in the receptor and ligand. These data provide compelling evidence that the hydroxyl group of Tyr106 of the TRH-R binds the TRH pyroglutamyl carbonyl group. To our knowledge, this represents the highest affinity, non-covalent bond yet observed between single functional groups of a GPCR and ligand and is the first delineation of a direct binding interaction between a residue in the transmembrane core of a GPCR and a specific moiety of a peptide agonist.

Amino Acid Sequence↗
PubMed1996

Mechanistic hypotheses for the activation of G-protein-coupled receptors.

G-protein-coupled receptors (GPCR) play an important role in the functioning of the nervous and endocrine systems. Intensive efforts devoted to mutational analyses of GPCR have greatly enhanced our understanding of the receptor-G-protein signalling pathway. Nonetheless, the lack of receptor structural data mandates that the mechanism of receptor activation can only be probed indirectly through hypothesis testing. Mechanistic models at two different levels, a thermodynamic model and a structural model, are reviewed here. A general thermodynamic model can be used as a framework for analyzing macroscopic experimental data, while a probability function based on a helical-rotation model can potentially provide a link between microscopic conformational changes and macroscopic rate constants and equilibrium constants. Conformational induction and conformational selection are two inseparable consequences of the receptor-binding system. Mechanistic models based on the integration of mutational data, spectroscopic data, and model simulation will form a foundation upon which further experiments can be designed, and consideration of both thermodynamic and structural principles will provide coherent insights into the receptor-activation process.

Binding Sites↗
PubMed1998

Molecular modelling of the vasopressin V2 receptor/antagonist interactions.

We predict some essential interactions between the V2 vasopressin renal receptor (V2R) and its selective peptide antagonist desGly9-[Mca1,D-Ile2,Ile4]AVP, and compare these predictions with the earlier ones for the non-peptide OPC-36120 antagonist- and the [Arg8]vasopressin (AVP) agonist-V2 receptor interactions. V2R controls antidiuresis in mammals and belongs to the superfamily of the heptahelical transmembrane (7TM) G protein-coupled receptors (GPCR)s. V2R was built, the ligands docked and the structures relaxed using advanced molecular modeling techniques. Both the agonist and the antagonists (no matter whether of peptide- or non-peptide type) appear to prefer a common V2R compartment for docking. The receptor amino-acid residues, potentially important in ligand binding, are mainly in the TM3-TM7 helices. A few of these residues are invariant for the whole GPCR superfamily while most of them are conserved in the subfamily of neurohypophyseal receptors, to which V2R belongs. Some of the equivalent residues in a related V1a receptor have been earlier reported as critical for the ligand affinity.

Amino Acid Sequence↗
PubMed1998

Identification of a novel G-protein coupled receptor expressed in distinct brain regions and a defined olfactory zone.

PCR-approaches with degenerated oligonucleotide primers have been employed in trying to identify novel members of the G-protein coupled receptor (GPCR) superfamily from rat brain. Screening a rat brain library with an amplification product showing some features of a GPCR gene led to the isolation of a full-length clone (RA1c); the encoded polypeptide comprises seven distinct hydrophobic stretches as well as several other hallmarks of GPCRs. Sequence comparison revealed a rather low but significant homology to GPCRs; RA1c shares about 30% sequence identity with various olfactory receptors and about 27% with several peptide receptors. By Northern blot and especially by in situ hybridization analysis it could be demonstrated that the RA1c receptor is expressed only in very distinct areas of the brain and in addition in a defined zone of the olfactory epithelium.

Amino Acid Sequence↗
PubMed2024

Early Events in β2AR Dimer Dynamics Mediated by Activation-Related Microswitches.

G-Protein-Coupled Receptors (GPCRs) make up around 3-4% of the human genome and are the targets of one-third of FDA-approved drugs. GPCRs typically exist as monomers but also aggregate to form higher-order oligomers, including dimers. β2AR, a pharmacologically relevant GPCR, is known to be targeted for the treatment of asthma and cardiovascular diseases. The activation of β2AR at the dimer level remains under-explored. In the current study, molecular dynamics (MD) simulations have been performed to understand activation-related structural changes in β2AR at the dimer level. The transition from inactive to active and vice versa has been studied by starting the simulations in the apo, agonist-bound, and inverse agonist-bound β2AR dimers for PDB ID: 2RH1 and PDB ID: 3P0G, respectively. A cumulative total of around 21-μs simulations were performed. Residue-based distances, RMSD, and PCA calculations suggested that either of the one monomer attained activation-related features for the apo and agonist-bound β2AR dimers. The TM5 and TM6 helices within the two monomers were observed to be in significant variation in all the simulations. TM5 bulge and proximity of TM2 and TM7 helices may be contributing to one of the early events in activation. The dimeric interface between TM1 and helix 8 were observed to be well maintained in the apo and agonist-bound simulations. The presence of inverse agonists favored inactive features in both the monomers. These key features of activation known for monomers were observed to have an impact on β2AR dimers, thereby providing an insight into the oligomerization mechanism of GPCRs.

Receptors, Adrenergic, beta-2↗
PubMed2026

Structural basis of β-arrestin coupling and transducer selectivity in PAC1R.

The pituitary adenylate cyclase-activating polypeptide receptor (PAC1R) is a class B G protein-coupled receptor (GPCR) that engages both G proteins and β-arrestins to mediate diverse signaling responses, yet how PAC1R adopts distinct intracellular conformations to achieve this transducer selectivity remains poorly understood. Here, we report the cryo-electron microscopy structure of PAC1R in complex with β-arrestin 1 (βarr1), revealing a core-engaged conformation. Comparison with the Gs-bound PAC1R structure shows that βarr1 engagement is associated with remodeling of the intracellular transmembrane bundle, including TM5 reorientation and inward movement of TM6, resulting in a receptor core geometry distinct from that of the G protein-bound state. Comparison with the βarr1-bound parathyroid hormone receptor 1 (PTH1R) structure further reveals both conserved and receptor-specific features of βarr1 engagement. Although outward displacement of the TM5 cytoplasmic end is observed in both PAC1R-βarr1 and PTH1R-βarr1 complexes, its specific direction and the resulting TM5-TM6 rearrangements differ between receptors, correlating with distinct βarr1 finger loop orientations within the receptor core. Together, these findings suggest that β-arrestin core engagement by class B GPCRs is accompanied by receptor-specific intracellular remodeling that may contribute to transducer selectivity in PAC1R.

Class B GPCR↗
PubMed2001

Peptide interactions with G-protein coupled receptors.

Peptide recognition by G-protein coupled receptors (GPCRs) is reviewed with an emphasis on the indirect approach used to determine the receptor-bound conformation of peptide ligands. This approach was developed in response to the lack of detailed structural information available for these receptors. Recent advances in the structural determination of rhodopsin (the GPCR of the visual system) by crystallography have provided a scaffold for homology modeling of the inactive state of a wide variety of GPCRs that interact with peptide messages. Additionally, the ability to mutate GPCRs and assay compounds of similar chemical structure to test a common binding site on the receptor provides a firm experimental basis for structure-activity studies. Recognition motifs, common in other well-studied systems such as proteolytic enzymes and major histocompatibility class receptors (MHC) are reviewed briefly to provide a basis of comparison. Finally, the development of true peptidomimetics is contrasted with nonpeptide ligands, discovered through combinatorial chemistry. In many systems, the evidence suggests that the peptide ligands bind at the interface between the transmembrane segments and the extracellular loops, while nonpeptide antagonists bind within the transmembrane segments. Plausible models of GPCRs and the mechanism by which they activate G-proteins on binding peptides are beginning to emerge.

Amino Acid Motifs↗
PubMed2001

Peptide fragments as models to study the structure of a G-protein coupled receptor: the alpha-factor receptor of Saccharomyces cerevisiae.

The alpha-factor tridecapeptide initiates mating in Saccharomyces cerevisiae upon interaction with Ste2p, its cognate G-protein coupled receptor (GPCR). This interaction is being used as a paradigm for understanding the structure and mechanism of activation of GPCRs by medium-sized peptides. In this article, the use of fragments of Ste2p to study its structure is reviewed. Methods of synthesis of peptides corresponding to both extramembranous and transmembrane domains of Ste2p are evaluated and problems that are encountered during synthesis and purification are described. The results from conformational analyses of the peptide fragments using fluorescence spectroscopy, CD, infrared spectroscopy, and NMR spectroscopy in organic-aqueous mixtures and in the presence of detergent micelles and lipid bilayers are critically reviewed. The data obtained to date provide biophysical evidence for the structure of different domains of Ste2p and indicate that peptides corresponding to these domains have unique biophysical tendencies. The studies carried out on Ste2p fragments indicate that valuable information concerning the structure of the intact receptor can be obtained by studying peptide fragments corresponding to domains of these polytopic integral membrane proteins.

Amino Acid Sequence↗
PubMed2001

G protein-coupled receptor signaling in human ductal pancreatic cancer cells: neurotensin responsiveness and mitogenic stimulation.

Neuropeptides and their corresponding G protein-coupled receptors (GPCRs) are increasingly implicated in the autocrine/paracrine stimulation of growth of human cancers. We report that neurotensin induced rapid Ca2+ mobilization from intracellular stores followed by Ca2+ influx in five human ductal pancreatic cancer cell lines: HPAF-II, Capan-1, Capan-2, PANC-1, and MIA PaCa-2. In addition, most cell lines exhibited Ca2+ responses to multiple neuropeptides including bombesin, bradykinin, cholecystokinin, and vasopressin and to bioactive lipids, including lysophosphatidic acid (LPA), that also act via GPCRs. The well-differentiated line HPAF-II responded to at least seven independent GPCR agonists. The concentrations of neurotensin required to induce half-maximal effects (EC50) in HPAF-II and PANC-1 cells were 5 and 8nM, respectively. Digital fluorescence image analysis to measure Ca2+ responses in single cells revealed that 90% or more of HPAF-II and PANC-1 cells responded to 10nM neurotensin. Addition of neurotensin to PANC-1 cells also induced rapid and dose-dependent extracellular-regulated protein kinase (ERK-1 and ERK-2) activation and subsequently, stimulated DNA synthesis. The signaling complexity of GPCRs uncovered by these studies reveals a new aspect in the biology of human pancreatic cancer and could offer the basis for new approaches to the treatment of this disease.

Bombesin↗
PubMed2000

Psychoactive cannabinoids and membrane signaling.

THC-like psychoactive cannabinoids permeate the lipid bilayer of the membrane, altering its physicochemical properties and activating phospholipases. As a result, an increased production of arachidonic acid occurs with its cascade of eicosanoids, including prostaglandins. In addition, THC and its psychoactive derivatives bind within the membrane in a stereospecific fashion, to a transmembrane G protein coupled receptor (GPCR) for which THC has a much higher affinity than the natural ligands, arachidonylethanolamide (AEA) and 2-arachidonyglycerol (2-AG). These natural lipid ligands may be considered signaling molecules which are generated in the membrane lipid bilayer. THC alters the physicochemical disposition of the lipid bilayer and interacts with the integral membrane protein receptors through alteration of the boundary lipid. This effect is distinct from the mechanism resulting from its persistent binding to a G protein coupled transmembrane receptor. THC does not interact directly with neurotransmitter receptors but alters their pharmacological response in an allosteric fashion. It is proposed that the binding of AEA and 2-AG to the G protein coupled transmembrane receptor possesses a physiological function which is to regulate the signaling between boundary lipids and membrane receptors in response to extracellular signals. AEA and 2-AG are eicosanoid signaling molecules which modulate the activity of G protein coupled transmembrane receptors. AEA and 2-AG should not be identified with synthetic ligand molecules dubbed 'endogenous cannabinoids' which are 'xenobiotics' with no physiological regulating function. THC deregulates persistently a basic signaling mechanism of the membrane lipid bilayer and of its integrated receptors with resulting impairment of cellular function of brain, heart and male gonads. Copyright 2000 John Wiley & Sons, Ltd.

Journal Article↗
PubMed2003

Growth retardation, developmental delay, distinctive face, multiple endocrine abnormalities, and adenylyl cyclase dysfunction: a new syndrome?

We report on a 17-year-old male with severe pre- and postnatal growth retardation, craniosynostosis, distinctive facial features, acanthosis nigricans, deafness, mental retardation and progressive multi-organ involvement, particularly of the endocrine system, including hypothyroidism, hypogonadism, transitory hypoparathyroidism, and insulin resistance. In order to find a common mechanism explaining these multiple abnormalities, we searched for a possible defect in the signal transduction pathways from membrane to nucleus involving G-protein coupled receptors (GPCR). Adenylyl cyclase activity was evaluated by assaying c-AMP in the patient's cultured fibroblasts stimulated with several drugs and toxins acting on different effectors upstream of adenylyl cyclase. The preliminary results indicate a reduced cAMP accumulation in the patient, neither caused by constitutive activation of Gi nor inhibition of Gs signaling, and probably resulting from an alteration in the adenylyl cyclase system. The differential diagnosis with syndromes showing common clinical features with our patient is discussed.

Adenylyl Cyclases↗
PubMed2004

Variants of the orexin2/hcrt2 receptor gene identified in patients with excessive daytime sleepiness and patients with Tourette's syndrome comorbidity.

The orexin-2/hypocretin-2 (OX2R) receptor gene is mutated in canine narcolepsy and disruption of the prepro-orexin/hypocretin ligand gene results in both an animal model of narcolepsy and sporadic cases of the human disease. This evidence suggests that the structure of the OX2R gene, and its homologue, the OX1R gene, both members of the G protein-coupled receptor (GPCR) family, and the gene encoding the peptide ligands, the prepro-orexin/hypocretin gene, may be variables in the etiology of sleep disorders. We report a single stranded conformational polymorphism (SSCP) analysis of the coding regions of these genes in idiopathic sleep disorder patients diagnosed with excessive daytime sleepiness (EDS) (n = 28), narcolepsy (n = 28), Tourette's syndrome/chronic vocal or motor tic disorder (n = 70), and control subjects (n = 110). Two EDS patients showed a Pro11Thr change. One Tourette's syndrome patient was found to have a Pro10Ser alteration. The Pro10Ser and Pro11Thr variants were not found in non-disease populations. Analysis of the ability of the mutant receptors to mobilize calcium compared to the wild-type receptor in response to orexin agonists indicated that they resulted in decreased potency at high (etaM) concentrations of orexin ligands. Further work is warranted to study the variability of the orexin/hypocretin system in a variety of disorders characterized by EDS.

Amino Acid Sequence↗
PubMed2001

Insect G protein-coupled receptors and signal transduction.

G protein-coupled receptors (GPCRs) are seven-transmembrane proteins (7-TM) that transduce extracellular signals into cellular physiological responses through the activation of heterotrimeric guanine nucleotide binding proteins (alpha beta gamma subunits). Their general properties are remarkably well conserved during evolution. Despite this general resemblance, a large variety of different signals are mediated via this category of receptors. Several GPCR-(sub)families have an ancient origin that is situated before the divergence of Protostomian and Deuterostomian animals. Nevertheless, an enormous diversification has occurred since then. The availability of novel sequence information is growing very rapidly as a result of molecular cloning experiments and of metazoan genome (Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens) and EST (expressed sequence tags) sequencing projects. The Drosophila Genome Sequencing Project will certainly have an important impact on insect signal transduction and receptor research. In parallel, convenient expression systems and functional assay procedures will be needed to investigate insect receptor properties and to monitor the effects of natural and artificial ligands. The study of the evolutionary aspects of G protein-coupled receptors and of their signaling pathways will probably reveal insect-specific features. More insight into these features may result in novel methods and practical applications. Arch.

Animals↗