Bioinformatics Research Laboratory, IBI Biosolutions Pvt. Ltd. India
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The DB-DRD4
Database Project |
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G-Protein Coupled Receptors
G-protein-coupled receptors (GPCRs) constitute a large and diverse family of proteins whose primary function is to transduce extracellular stimuli into intracellular signals. They are among the largest and most diverse protein families in mammalian genomes. On the basis of homology with rhodopsin, they are predicted to contain seven membrane-spanning helices, an extracellular N-terminus and an intracellular C-terminus. This gives rise to their other names, the 7-TM receptors or the heptahelical receptors. GPCRs transduce extracellular stimuli to give intracellular signals through interaction of their intracellular domains with heterotrimeric G proteins. This class of membrane proteins can respond to a wide range of agonists, including photon, amines, hormones, neurotransmitters and proteins. Some agonists bind to the extracellular loops of the receptor, others may penetrate into the transmembrane region.
The presence of GPCRs in the genomes of bacteria, yeast, plants, nematodes and other invertebrate groups argues in favor of a relatively early evolutionary origin of this group of molecules. The diversity of GPCRs is dictated both by the multiplicity of stimuli to which they respond, as well as by the variety of intracellular signalling pathways they activate. These include light, neurotransmitters, odorants, biogenic amines, lipids, proteins, amino acids, hormones, nucleotides, chemokines and, undoubtedly, many others. In addition, there are at least 18 different human G proteins to which GPCRs can be coupled. These G proteins form heterotrimeric complexes with Gß subunits, of which there are at least 5 types, and G subunits, of which there are at least 11 types.
Signal moleculesA wide variety of ligands use GPCRs to stimulate cytoplasmic and nuclear targets through heterotrimeric G-protein-dependent and -independent pathways.
Biogenic amines: noradrenaline, dopamine, 5-HT, histamine, acetylcholine, epinephrine, norepinephrine
G-protein Coupled Receptors Classification
GPCRs' sequences can be grouped into three distinct families, A, B and C, on the basis of sequence similarity. Sequences within each family generally share over 25% sequence identity in the transmembrane core region, and a distinctive set of highly conserved residues and motifs. Among the three families, little similarity is evident beyond the predicted 7TM architecture.
This family includes the receptors for light (rhodopsin) and adrenaline (adrenergic receptors) and most other 7TM receptor types, including the olfactory subgroup. The olfactory receptors constitute most of these sequences, but nearly 200 non-olfactory 7TM receptors that recognize over 80 distinct ligands have also been functionally characterized.
This family contains only ~25 members, including the receptors for the gastrointestinal peptide hormone family (secretin, glucagon, vasoactive intestinal peptide (VIP) and growth-hormone-releasing hormone), corticotropin-releasing hormone, calcitonin and parathyroid hormone. All family B receptors seen to couple mainly to activation of the effector adenylyl cyclase through the G protein Gs.
Family C contains the metabotropic glutamate receptor family, the GABA receptor, and the calcium-sensing receptor, as well as some taste receptors. All family C members have a very large extracellular amino terminus that seems to be crucial for ligand binding and activation.To date, the only member of the receptor superfamily for which a crystal structure has been solved is rhodopsin. This structure, which corresponds to the inactive receptor, confirms the presence of an anticlockwise bundle of 7TM alpha helices (viewed from the intradiscal or extracellular side) that are connected by loops of varying lengths.
general structure: N-terminal segment, seven TMs, Three exoloops, three-four cytoloops, and C-terminal segment.GPCRs are known for their involvement in physiological functions including neurotransmission, vision, olfaction, hormone action, platelet aggregation, and leukocyte chemotaxis. Induction of these diverse biological functions results from the activation of a collection of heterotrimeric G-proteins, which consist of alpha subunits and closely associated beta-gamma subunits. The alpha subunit is responsible for GTP and GDP binding and for GTP hydrolysis, whereas the beta and gamma subunits are associated in a tightly linked beta-gamma complex.
The complexity of the signaling pathways initiated by GPCRs is illustrated by the presence of numerous G-proteins, including 18 alpha subunits, which can be classified into four groups, 12 beta subunits, and 5 gamma subunits.G proteins are generally referred to by their alpha subunits. So, the Gs heterotromeric complex contains Galphas; Gq contains Galphas; and so on. Four distinct gamma subunit subfamilies are recognized. The four major families of G-protein are as follows:
Family Some Member Action mediated Functions I Gs α Activate adenylyl cyclase, Ca+2 channels Golf α Activate adenylyl cyclase in olfactory sensory neuron II Gi α Inhibit adenylyl cyclase ßγ Activates K+ channel Go ßγ Activates K+ channel, inactivate Ca+2 channels α and ßγ Activates phospholipase C-ß Gt (transducin) α Activates cyclic GMP phosphodiesterase in vertebrate photoreceptors III Gq α Activates phospholipase C-ß IV G12 α Activates Rho guanine-nucleotide exchange factors (GRFs) In 1971, Martin Rodbell conceived the idea taht a guanine-nucleotide regulatory protein functionally conncets receptors with effectors in the context of hormonal (glucagon) stimulation of the adenylyl cyclase system, generating the second messenger cyclic AMP.
Both the alpha subunit and the beta-gamma dimer signal through the activation, or inhibition, of an ever-expanding list of effectors. Agonist activation of the receptors induces conformational changes which are, as yet, poorly understood, but whcih seem to involve, at minimum, rearrangements of membrane helices 6 and 3. This 'activated receptor' can interact with the heterotrimeric G protein, and serves as a GEF to promote GDP dissociation, and GTP binding and activation. Receptors vary in their degree of agonist-independent or constitutive activity to couple to G proteins, and receptor mutants resulting in augmented activity have been found in numerous diseases.
In the current model, the activated heterotrimer dissociates into an alpha subunit and a beta-gamma dimer, both of which have an independent capacity to regulate separate effectors. Hydrolysis of GTP to GDP - a process that is now known to be regulated by RGS (regulator of G-protein signalling) proteins - leads to reassociation of the heterotrimer and termination of the activation cycle. However, much controversy has surrounded the issue of whether physical dissociation of alpha from beta-gamma actually occurs during G-protein activation, and the issue remains unsettled.
gpDB: a database of G-proteins and their interaction with GPCRs