GPCR full form; G-protein-coupled receptors (GPCRs) are the biggest and most diversified collection of membrane receptors in eukaryotes. These cell surface receptors act like an inbox for communications in the form of light energy, peptides, lipids, carbohydrate, and proteins. Cells receive these messages to alert them of the presence or absence of life-sustaining light or nutrients in their surroundings, or to relay information from other cells. They are also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLRs), which are cell surface receptors that detect chemicals outside the cell and activate physiological responses. They are known as seven transmembrane receptors because they bind to G proteins and cross through the cell membrane seven times.
GPCRs are involved in a wide range of processes in the human body, and a better understanding of these receptors has had a significant impact on modern medicine. In fact, experts believe that GPCRs are involved in the action of one-third to half of all marketed medications.
GPCRs have an extracellular N-terminus, seven transmembranes (7-TM) -helices (TM-1 to TM-7) coupled by three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3), and an intracellular C-terminus. The GPCR forms a barrel-like tertiary structure within the plasma membrane, with the seven transmembrane helices forming a cavity that serves a ligand-binding domain that is frequently covered by EL-2.
However, larger ligands (e.g., proteins or big peptides) may interact with the extracellular loops or, in the case of class C metabotropic glutamate receptors (mGluRs), the N-terminal tail, as shown by the class C metabotropic glutamate receptors (mGluRs). The long N-terminal tail of class C GPCRs, which also comprises a ligand-binding region, distinguishes them from other GPCRs. When glutamate binds to a mGluR, the N-terminal tail undergoes a conformational shift that allows it to connect with the extracellular loop and TM domain residues.
All three types of agonist-induced activation result in a change in the relative orientations of the TM helices (similar to a twisting motion), resulting in a broader intracellular surface and "disclosure" of intracellular helices and TM domains critical to signal transduction function (i.e., G-protein coupling). Inverse agonists and antagonists may attach to a variety of locations, but their ultimate function must be to prevent the TM helix from reorienting.
The structure of GPCRs' N- and C-terminal tails could have crucial functions other than ligand binding. M3 muscarinic receptors, for example, have an adequate C-terminus, but the six-amino-acid polybasic (KKKRRK) domain in the C-terminus is required for pre assembly with Gq proteins. The C-terminus, in particular, frequently contains serine (Ser) or threonine (Thr) residues, which, when phosphorylated, increase the intracellular surface's affinity for the binding of scaffolding proteins known as -arrestins (-arr).
Once attached, -arrestins sterically impede G-protein coupling and may recruit other proteins, resulting in the formation of signalling complexes that are implicated in the activation of the extracellular signal-regulated kinase (ERK) pathway or receptor endocytosis (internalization). Because these Ser and Thr residues are frequently phosphorylated as a result of GPCR activation, -arr-mediated G-protein dissociation and GPCR internalisation are essential processes of desensitisation. Furthermore, internalised "mega-complexes" containing a single GPCR, -arr(in the tail conformation), and heterotrimeric G protein exist and may be responsible for endosome protein signalling.
Palmitoylation of one or more locations of the C-terminal tail or intracellular loops is another common structural feature among GPCRs. Palmitoylation is the addition of hydrophobic acyl groups to cysteine (Cys) residues, which has the effect of directing the receptor to cholesterol- and sphingolipid-rich microdomains of the plasma membrane known as lipid rafts. Because many GPCR downstream transducer and effector molecules (including those implicated in negative feedback pathways) are similarly localised to lipid rafts, fast receptor signalling is facilitated.
GPCRs respond to extracellular signals mediated by a wide range of agonists, from proteins to biogenic amines to protons, but they all use a G-protein coupling mechanism to transmit the signal. A guanine-nucleotide exchange factor (GEF) domain, which is predominantly produced by a mixture of IL-2 and IL-3, as well as neighbouring residues of the related TM helices, enables this.
G Protein-Coupled Receptors Examples: Beta-adrenergic receptors that bind epinephrine; prostaglandin E2 receptors that bind inflammatory compounds called prostaglandins; and rhodopsin, which contains a photoreactive molecule called retinal that responds to light signals received by rod cells in the eye, are all examples of GPCRs.
GPCRs interact with G proteins in the plasma membrane, as their name suggests. When a signalling molecule interacts with a GPCR, the GPCR undergoes a conformational shift. The GPCR and a neighbouring G protein then interact as a result of this alteration.
G proteins are specialised proteins that can bind the guanosine triphosphate (GTP) and guanosine diphosphate (GDP) nucleotides (GDP). Some G proteins, such as the signalling protein Ras, are single-subunit proteins. The G proteins that interact with GPCRs, on the other hand, are heterotrimeric, which means they have three subunits: an alpha subunit, a beta subunit, and a gamma subunit. Lipid anchors link two of these subunits — alpha and gamma — to the plasma membrane.
Depending on whether the protein is active (GTP) or inactive (GDP), the alpha subunit of a G protein binds GTP or GDP (GDP). GDP binds to the alpha subunit in the absence of a signal, and the complete G protein-GDP complex binds to a neighbouring GPCR. This configuration lasts until the GPCR is joined by a signalling molecule. A change in the GPCR's conformation activates the G protein at this moment, and GTP physically replaces the GDP linked to the alpha subunit. As a result, the G protein subunits split into two: a GTP-bound alpha subunit and a beta-gamma dimer.
Both components are still fixed to the plasma membrane, but they are no longer tethered to the GPCR, allowing them to interact with other membrane proteins laterally. As long as the alpha subunits of G proteins are linked with GTP, they stay active. When this GTP is hydrolyzed back to GDP, the subunits reassemble into an inactive heterotrimer, and the complete G protein reassociates with the now-defunct GPCR. G proteins function as a switch, being turned on and off by signal-receptor interactions on the cell surface.
When a G protein is active, its GTP-bound alpha subunit and beta-gamma dimer can interact with other membrane proteins involved in signal transduction to relay messages throughout the cell. Different enzymes that make second messengers, as well as certain ion channels that allow ions to behave as second messengers, are specific targets for activated G proteins. Some G proteins enhance these targets' activity, while others inhibit it. The alpha, beta, and gamma subunits of G proteins are encoded by numerous genes in vertebrate genomes. These genes encode a variety of subunits that assemble in a variety of ways to form a varied family of G proteins.
An external signal, such as a ligand or another signal mediator, activates the G protein-coupled receptor. This causes a conformational shift in the receptor, resulting in G protein activation. The type of G protein has an additional effect. G proteins are then inactivated by RGS proteins, which are GTPase activating proteins.
GPCRs have one or more receptors for the following ligands: sensory signal mediators (e.g., light and olfactory stimulatory molecules); adenosine, bombesin, bradykinin, endothelin, γ-aminobutyric acid (GABA), hepatocyte growth factor (HGF), melanocortins, neuropeptide Y, opioid peptides, opsins, somatostatin, GH, tachykinins, members of the vasoactive intestinal peptide family, and vasopressin; biogenic amines (e.g., dopamine, epinephrine, norepinephrine, histamine, serotonin, and melatonin); glutamate (metabotropic effect); glucagon; acetylcholine (muscarinic effect); chemokines; lipid mediators of inflammation (e.g., prostaglandins, prostanoids, platelet-activating factor, and leukotrienes); peptide hormones (e.g., calcitonin, C5a anaphylatoxin, follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH), neurokinin, thyrotropin-releasing hormone (TRH), and oxytocin); and endocannabinoids.
Orphan receptors are GPCRs that serve as receptors for stimuli that have yet to be discovered.
GPCR ligands, on the other hand, often bind within the transmembrane domain, unlike other types of receptors that have been investigated and where ligands attach outside to the membrane. Protease-activated receptors, on the other hand, are triggered by the cleavage of a portion of their extracellular domain.
The receptor's signal transduction through the membrane is not totally understood. The GPCR is known to be linked to a heterotrimeric G protein complex in its inactive state. When an agonist binds to a GPCR, the receptor undergoes a conformational shift that is conveyed to the bound G subunit of the heterotrimeric G protein through protein domain dynamics. The activated G subunit exchanges GTP for GDP, resulting in the G subunit's separation from the G dimer and from the receptor. The fragmented G and G subunits engage with other intracellular proteins to continue the signal transduction cascade, while the released GPCR can rebind to another heterotrimeric G protein to form a new complex ready to start a new round of signal transduction.
A receptor molecule is thought to be in a conformational balance between active and inactive biophysical states. Ligand binding to the receptor may cause the equilibrium to shift toward active receptor states. There are three categories of ligands: Agonists are ligands that cause the equilibrium to shift in favour of active states, inverse agonists are ligands that cause the equilibrium to move in favour of inactive states, and neutral antagonists are ligands that have no effect on the equilibrium. It's still unclear how the active and inactive states differ from one another.
G-protein Activation/Deactivation Cycle
The GEF domain may be attached to an inactive -subunit of a heterotrimeric G-protein when the receptor is inactive. These "G-proteins" are a trimer of subunits (known as G, G, and G, respectively) that are rendered inactive when reversibly attached to Guanosine diphosphate (GDP) (or, alternatively, no guanine nucleotide) but active when bound to guanosine triphosphate (GTP). The GEF domain allosterically activates the G-protein by enabling the exchange of a molecule of GDP for GTP at the G—subunit protein's upon receptor activation. The cell maintains a 10:1 cytosolic GTP: GDP ratio to ensure GTP exchange. The G-protein subunits detach from the receptor and from each other at this stage, resulting in a G-GTP monomer and a tightly coupled G dimer that can now control the activity of other intracellular proteins. The palmitoylation of G and the presence of an isoprenoid moiety that has been covalently attached to the C-termini of G, however, limit the amount to which they can spread.
Because G can also hydrolyze GTP to GDP, the inactive form of the -subunit (G-GDP) is eventually regenerated, allowing reassociation with a G dimer to create the "resting" G-protein, which can bind to a GPCR and await activation. The effects of another family of allosteric modifying proteins known as Regulators of G-protein Signaling, or RGS proteins, which are a form of GTPase-Activating Protein, or GAP, often speed up the rate of GTP hydrolysis. Many of the key effector proteins (e.g., adenylate cyclases) that are activated/inactivated by G-GTP also exhibit GAP activity. GPCR-initiated signalling has the ability to self-terminate even at this early stage in the process.
The signalling pathways activated by GPCRs are constrained by the GPCR's primary sequence and tertiary structure but are ultimately controlled by the conformation maintained by a particular ligand and the availability of transducer molecules. GPCRs are thought to use two sorts of transducers at the moment: G-proteins and -arrestins. The majority of signalling is ultimately dependent on G-protein activation because -arr's have a high affinity only for the phosphorylated version of most GPCRs. The possibility of contact, on the other hand, allows for G-protein-independent signalling.
There are three main G-protein-mediated signalling pathways, each mediated by four sub-classes of G-proteins (Gαs, Gαi/o, Gαq/11, and Gα12/13), which are characterised by sequence homology. Each sub-class of G-protein consists of several proteins, each of which is the result of multiple genes or splice variants, which can result in modest to significant variances in signalling capabilities, although they appear to be categorised into four classes in general. These classes are defined by the isoform of their -subunit because the signal-transducing properties of the different potential combinations do not appear to differ much.
While most GPCRs are capable of activating multiple G-subtypes, they have a preference for one over the other. Functional selectivity occurs when the subtype activated is dependent on the ligand bound to the GPCR (also known as agonist-directed trafficking, or conformation-specific agonism). However, because any single agonist may be capable of maintaining more than one conformation of the GPCR's GEF domain during the course of single contact, it may also trigger activation of numerous different G-proteins. In addition, if the chosen isoform of Gα is not available, a conformation that activates one isoform of Gα may activate another. In addition, feedback mechanisms may cause receptor changes (such as phosphorylation) that modify G-protein preference. Regardless of these intricacies, the GPCR's preferred coupling partner is usually determined by the G-protein that is most clearly activated by the endogenous ligand in most physiological or experimental situations.
GPCRs may communicate through G-protein-independent methods, and heterotrimeric G-proteins may perform functional roles independent of GPCRs, despite the fact that they are traditionally assumed to only work together. Many proteins already listed for their functions in G-protein-dependent signalling, such as -arrs, GRKs, and Srcs, may signal independently through GPCRs. For example, -arrestin signalling mediated by the chemokine receptor CXCR3 was found to be required for full effectiveness chemotaxis of activated T cells. Further scaffolding proteins involved in GPCR subcellular localization (e.g., PDZ-domain-containing proteins) may also operate as silencing proteins.
The cAMP signal pathway and the phosphatidylinositol signal pathway are the two main signal transduction pathways involving G protein-linked receptors.
cAMP Signal Pathway-
Stimulative hormone receptor (Rs) or inhibitory hormone receptor (Ri); stimulative regulative G-protein (Gs) or inhibitory regulative G-protein (Gi); adenylyl cyclase; protein kinase A (PKA); and cAMP phosphodiesterase are the five key components of the cAMP signalling pathway.
The stimulative hormone receptor (Rs) can bind with stimulative signal molecules, whereas the inhibitory hormone receptor (Ri) can interact with inhibitory signal molecules.
Stimulative regulative G-protein is a G-protein that is related to the stimulative hormone receptor (Rs), and its component can stimulate the activity of an enzyme or other intracellular processes when activated. Inhibitory regulative G-protein, on the other hand, is coupled to an inhibitory hormone receptor, and its subunit could impede the action of an enzyme or other intracellular processes when activated.
Adenylyl cyclase is a 12-transmembrane glycoprotein that uses the cofactor Mg2+ or Mn2+ to catalyse the conversion of ATP to cAMP. The cAMP generated is a second messenger in cellular metabolism and a protein kinase A allosteric activator.
Protein kinase A regulates cell metabolism by phosphorylating particular committed enzymes in the metabolic pathway, making it a key enzyme in cell metabolism. It can also control the expression of particular genes, cellular secretion, and membrane permeability. Two catalytic and two regulatory subunits make up the protein enzyme. The complex is inactive when there is no cAMP present. When cAMP binds to regulatory subunits, their conformation changes, causing the regulatory subunits to dissociate, activating protein kinase A and allowing for additional biological consequences.
cAMP phosphodiesterase, an enzyme that converts cAMP to 5'-AMP and inactivates protein kinase A, can then terminate these impulses.
Phosphatidylinositol Signal Pathway-
The extracellular signal molecule interacts with the G-protein receptor (Gq) on the cell surface and activates phospholipase C, which is found on the plasma membrane, in the phosphatidylinositol signal pathway. Phosphatidylinositol 4,5-bisphosphate (PIP2) is hydrolyzed by lipase into two-second messengers: inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 interacts to the IP3 receptor in the smooth endoplasmic reticulum and mitochondrial membranes, which opens Ca2+ channels. DAG aids in the activation of protein kinase C (PKC), which phosphorylates a variety of other proteins, altering their catalytic activity and causing cellular reactions.
Ca2+ has remarkable effects: it cooperates with DAG in activating PKC and can activate the CaM kinase pathway, in which the calcium-modulated protein calmodulin (CaM) binds Ca2+, undergoes a conformational change, and activates CaM kinase II, which has the unique ability to increase its binding affinity to CaM by autophosphorylation, rendering CaM unavailable for the activation of other enzymes. The kinase then phosphorylates and regulates the activity of target enzymes. Ca2+-CaM, which is also a regulatory subunit of adenylyl cyclase and phosphodiesterase in the cAMP signal pathway, connects the two signal pathways.
GPCRs have a role in a number of physiological processes. The following are some examples of their physiological roles:
The Visual Sense: Opsins convert electromagnetic radiation into cellular messages through a photoisomerization event. Rhodopsin, for example, accomplishes this by converting 11-cis-retinal to all-trans-retinal. Opsins convert electromagnetic radiation into cellular messages through a photoisomerization event. Rhodopsin, for example, accomplishes this by converting 11-cis-retinal to all-trans-retinal.
The Gustatory Sense (Taste): Gustducin is released by GPCRs in taste cells in reaction to bitter, umami, and sweet-tasting stimuli.
The Sense of Smell: The olfactory epithelium has receptors that bind odorants (olfactory receptors) and pheromones (vomeronasal receptors).
Behavioral and Mood Regulation: Serotonin, dopamine, histamine, GABA, and glutamate are among the neurotransmitters bound by receptors in the mammalian brain.
Regulation of Immune System Activity and Inflammation: Histamine receptors bind inflammatory mediators and engage target cell types in the inflammatory response; chemokine receptors bind ligands that promote intercellular communication between immune system cells. GPCRs play a role in immunological modulation as well, controlling interleukin induction and inhibiting TLR-induced immune responses in T cells, for example.
1. What is the Role of the G Protein-coupled Receptor?
Our senses of vision, smell, taste, and pain are all mediated by G protein-coupled receptors (GPCRs). They have a role in cell recognition and communication, and as a result, they've become a popular pharmacological target superfamily.
2. Why is GPCR Important?
The GPCR family comprises receptors that detect light, taste, odours, hormones, pain, neurotransmitters, and a variety of other stimuli. In other words, GPCR signalling is at the heart of most physiological processes. This is why the GPCR family is so important in the pharmaceutical industry.