See also G proteins

G protein-coupled receptors(GPCRs) comprise a large superfamily of receptors which are prevalent through-out the human body, comprising about 60% of known cellular receptor types. GPCRs were originally defined as receptors that transduce signals from the extracellular compartment to the interior through biochemical processes involving GTP-binding proteins. GPCRs mediate signal transduction across the cell membrane for a very wide range of endogenous ligands. The prototypical GPCR is comprised of a seven-transmembrane spanning receptor which is coupled to a heterotrimeric-G-protein complex. The extracellular transmembrane segments determine receptor ligand specificity, and the activation of the heterotrimeric-G-protein complex mediates downstream signaling pathways. Althouh G protein-coupled receptors display significant sequence homoloyg in the transmembrane domains, homology is almost nonexistent in the amino- and carboxyl-temrinal domains and in the large cytoplasmic lopp that connects transmembrane helices 5 and 6.

G protein-coupled receptors (GPCrs) are so named because the receptors act by coupling with a G protein.

GPCRs mediate the majority of cellular resposnes to extenal stimuli, including light, odors, hormones, and growth factors. (Kobilka, “The molecular basis of G protein-coupled receptor activation” Annu Rev Biochem, 2018, 897-919).

Structure 

The heterotrimeric-G-protein complex consists of an alpha subunit, and a dimerized beta-gamma subunit.

While all GPCRs display the canonical seven helical transmembrane (TM) structure, different GPCR classes have substantial differences in other aspects of their architecture, especially at their extracellular N-terminal tails, intracellular C-terminal tails, and intracellular loops. Post-translational modifications (PTMs) of GPCRs include glycosylation, tyrosine sulfation, serine and threonine phosphorylation, and acylation. GPCRs derive their name from the ability to bind heterotrimeric (αβγ) guanine nucleotide-binding regulatory proteins (G proteins) to cause guanine-nucleotide exchange. The active GTP-bound form of the G protein α subunit or the free G protein βγ heterodimer subunit can then interact with downstream cellular effector enzymes or channels. G proteins are classified according to conserved primary structures of the Gα subunits (αi/o, αs, α12/13, and αq/11) and generally initiate different signaling cascades. (Sacamar, “Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins” Pharmacol. Review, 2023)

GPCR Signalling:

GPCRs are classic allosteric proteins: Agonist binding at one site that is accessed form the extracellular space, termed the orthosteric site, promotes binding to another partner (e.g., a heterotrimeric G protein) at hte cytoplasmic side. The coupled equilibrium of agonist and G protein binding is well known: Not only does agonist binding promote binding of the receptor to a G protein, but the affintiy of the agonist for the receptor is increased by the G protein. (Kobilka, “The molecular basis of G protein-coupled receptor activation” Annu Rev Biochem, 2018, 897-919).

Upon ligand-receptor interaction, GTP is exchanged for GDP on the alpha subunit resulting in the release of the heterotrimeric-G-protein complex from the receptor and dissassociation of the alpha -GTP subunit and the beta-gamma dimer. Both the alpha -GTP subunit and the beta-gamma dimer can then independently induce secondary cell signaling pathways. The dephosphorylation of the alpha  subunit terminates the activation of intracellular signaling, and favors high-affinity binding of the alpha  subunit to free beta-gamma dimers. This results in the reassembly of the trimeric complex, which is then recycled to the cell surface receptor permitting subsequent signaling events.

GPCRs are composed of a complex of Galpha, G beta and G gamma subunits. Upon recetpor activaiton the receptor acts as a guanine nucleotide exhcange factor for the G-alpha subunit, inducing release of guanosine diphosphate in exchange for GTP. This induced dissocaition of the Gal-ha-GTP subunit from the Gbeta-alpha complex, allowing each of these units to independently interat with a wide range of effectors to regualted second messenger levels, protein kinases, and other pathways to impaact idfferent cellular functions. (Rockman, “G Protein-coupled receptors: a century of research and discovery” Circulation Research, 2024)

The duration and intensity of the signaling events is dependent on the rate of GTP hydrolysis, which in turn is dependent on both the intrinsic GTPase capacity of the alpha  subunit as well as the activity of intracellular regulators of G protein signaling (RGS) proteins which directly hydrolyze GTP to GDP.

Canonical GPCR activation of Gαs is associated with generation of the second messenger cAMP, whereas Gαi activation reduces cAMP levels. Gαq activation is associated with generation of inositol 1,4,5-trisphosphate (IP3) and release of intracellular calcium (Ca2+). Several effectors downstream of GPCR activation can mediate activation of extracellular signal-regulated kinase (ERK) signaling pathways. Phosphorylation of the C-terminal tail of the active GPCR by GPCR kinases (GRKs) creates a substrate for the binding of adaptor/signaling molecules called nonvisual arrestins (β-arrestins). β-arrestin binding turns off G protein signaling and, in some cases, initiates separate signaling cascades. (Sacamar, “Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins” Pharmacol. Review, 2023)

Classification/Examples of G Protein-Coupled Receptors

About 800 GPCRs are encoded by the human genome. The majority belong to the so-called family A or rhodopsin-like receptors, which is the most well studied group. (Kobilka, “The molecular basis of G protein-coupled receptor activation” Annu Rev Biochem, 2018, 897-919).

GPCRs are alocated in five families. Upon stimulation by an extracellular stimuli (ligand), GPCRs undergo conformational changes, and triggers downstream intracellular signals by coupling the G proteins, causing a wide range of both physiological and pathological prcoesses.

The G protein-coupled receptors (GPCRs) superfamily comprises approximately 800 distinct receptor genes, of which approximately 400 are nonolfactory receptors. GPCRs respond to diverse classes of agonist ligands and can trigger or modulate a wide range of intracellular responses. For example, activated GPCR signaling cascades can induce changes in second-messenger levels, activate cellular kinases and other regulatory enzymes, regulate ion channels, and alter gene transcription. (Sacamar, “Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins” Pharmacol. Review, 2023)

GPCRs make up the targets of about 30% of all FDA approved drugs. There are over 200 GPCRs expressed in the heart, and drugs targetting many of these GPCRs expressed in the cardiosascular system are maintstays of clinical treatment. (Rockman, “G Protein-coupled recetpors: a century of research and discovery” Circulation Research, 2024)

Class B (Secretin family); Incretin Hormone Receptors:

GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) are 2 peptide hormones released by the gut that are responsible for mediating increased insulin secretion by the pancreas in response to an oral glucose load. Their receptors are expressed on the beta cells in pancreatic islets and are also expressed in the heart, vasculature, intestines, kidney and grain. The GLP-1R is GalphaS and Galphaq coupled while the GIPR (GIP receptor) only signals through GalphaS. The relative ability of both receptors to signal through GalphaS may be altered during diabetes. Both receptors can also signal through Beta-arrestin. (Rockman, “G Protein-coupled recetpors: a century of research and discovery” Circulation Research, 2024)

Insulin is an essential hormone that facilitates glucose uptake in peripheral tissues, promoting blood glucose control, and basic cellular functions. Following nutrient ingestion, the postprandial insulin secretion is mainly caused by a rise in plasma glucose and a nutrient-induced secretion of the gastrointestinal hormones, glucagon like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 and GIP are responsible for the incretin effects, which is the potentiation of glucose-induced insulin secretion seen when nutrients pass the gastrointestinal tract. GLP-1 and GIP exert their physiological actions via stimulation of the two G protein coupled receptors (GPCRs): GLP-1R and GIPR. Gasbjert, Peptides 151 (2022) 170749.)

–GLP-1R:

In addition to being located in the pancreatic endocrine islets, GLP-1R is epxressed in the gastrointestinal tract, the cardiosvascular syste, brain, kidneys and immune cells. It consists of 3 domains, the extracellular N-temrinus, the transmembrane core domain, and an intracellular C-temrinal domain. The large N-temrinus binds the Cterminus of the GLP-1 peptide, while the transmembrane domain binds the N-temrinus of the GLP-1 peptide. GLP-1R belongs to the class B1 GPCRs, which are activated by a two-step binding mechanism upon binding of ther endogenous ligands. Accoridng to this model, the ligand binding to the receptor is initiated by an interaction of the extra-cellular domain ECD of the receptor with the C-terminal alpha helical part of the ligand. Then, the ligand N-terminus is docked into the transmembrane domain TMD of the receptor. This results in receptor activaiton and downward signaling through G proteins. (Gasbjert, Peptides 151 (2022) 170749.)

The corresponding ligand, GLP-1 (glucoagon like peptide-1) , is secreted from enteroendocrine L cells in response to nutrient stimulation, and its activation of GLP-1Rs result in insulin secretion and inhibited glucagon secretion from receptors expressed at beta cells and alpha cells, respectivly, reduced gastric emptying rate from GLP-1Rs in the ventricle and stimulation of satiety from receptor expressed in the central nervous system. Many drugs targeting the GLP-1R have been developed for the treamtent of type 2 diabetes and obesity such as semaglutide. Compared to endogenous GLP-1, these all have prolonged elimination half-lives and most often longer receptor residence times. GLP-1R activation in pancreatic beta cells promote recruitment and activation of Galphas protein leading to adenylate cyclase-mediated cAMP production, elevation of Ca2+ and ERK1/2 phosphorylation. cAMP production lead to activation of protein kinase A (PKA) as well as exchange protein directly activated by cAMP (EPAC) and is directly involved in increasing proinsulin gene transcription and subsequent insulin secretion. (Gasbjert, Peptides 151 (2022) 170749.) GLP-1 is a 30 or 31 amino acid long peptide homrone mainly secreted by 3 tissues in the human body, enteroendocrine L cells in the distal instesting, alpha cells in the pancreas, and the central nervous system. Through its interaction with the GLP-1 receptor, GLP-1 participates in the regulation of glucose homeostasis. (Glucagon like peptide-1 receptor agonists (GLP-1RAs) are emerging glucose control drugs, which are widely used in the treamtent of T2MD. Due to the wide distribution of GLP-1R, GLP-1RAs also have a wide range of pharmacological effects.  (Zhang, frontiers in Endocrinology, 12, 2021).

Although GLP-1R agonists were originally developed and approved for glycemic control in the setting of diabetes, incretin recetpor agonsits have been found to improve a much wider range of ehalth outcomes. For example, GLP-1R agonsits has been shown to improved a number of cardiovascular biomarekrs and reduce all-cause major adverse cardiovascular events, a composite outcome including nonfatal myocardial infarction, stroke, and cardiovascular death. Additionally, in the  SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) and STEP-HFpEF (Semaglutide Treatment Effect in People with Obesity and Heart Failure with Preserved Ejection Fraction) clinical trails, the GLP-1R agonist semaglutide improved cardiovascular outcomes in patients with obesity in the absence of diabetes. In the wake of these promising findings, GLP-1 receptor agonsits have been recognized as the breakthorugh of the year 2023. (The mechanism by which GLP-1R agonists promote beneficial cardiovascular outcomes is multifactorial. The treatment of obesity, which increases cardiovascular disease risk through the development of dyslipidemia, type 2 diabetes, and hypertension, likely plays a role. Additionally some of their activities apepar to be mediated through direct actions on receptors expressed in the cardiovascular system. Currently, under development are additional incretin receptor agonists. Here, the focus has been on small molecule agonsits of incretin receptors that have improved oral bioavailability compared with currently existing peptide based agonsits, the development of triple agonists that have the ability to activate GLP, GIP and glucagon receptors and which appear to have greater efficacy for glycemic control and weight loss and third, the role biosed agonism plays in the physiological response to these ligands. Physiologically, insulin secretion in pancreatic beta cells in response to incretin stimulation is medaited by GalphaS, Galphaq and Beta-arrestin. Rockman, “G Protein-coupled recetpors: a century of research and discovery” Circulation Research, 2024)

–GIPR:

To stimulate insluin secretion after nutrient ingetion, GIP binds to and activates the GIPR on the beta cell surface. As for the GLP-1R above, the activaiton of GIPR promotes recruitment and acitvatuon of the G-alpha-s protein, which in turn activates the adenylate cyclass to stimulate cAMP protein. Due to tbe therpaeutic potential of increased insulin secretion and improved beta cell health in patients with type 2 diabetes, GLP-1R/GIPR co-agonists are now in drug development progams. Impressively, syntergistic effects have been resported  for a GLP-1R-GIPR co-agonist tirzepatide, promoting higher insulin response than seaprate administraiton of each hormone. Tirzepatide has potent glucose lowering and weight loss effects compared to teh established GLP-1R agonists and demonstrates dose dependent reduciton in HbA1c in paitents with type 2 diabetes. (Gasbjert, Peptides 151 (2022) 170749.)

Adrenoreceptors: are receptors fundamental to normal cardiovascular physiology. The use of naturally existing adrenergic receptor ligands such as the alkaloid ephedrine from the herb Ephedra can be traced back to ancient Asia. Epinephrine is actually one fo the first human hormones to be isolated. (Rockman, “G Protein-coupled recetpors: a century of research and discovery” Circulation Research, 2024)

The Beta1AR and Beta2AR are the predominant adrenergic receptor subtypes expressed in the heart, while the Beta3AR is primarily expressed in adipose tissue. The importance of Beta-adrenergic signaling in cardiovascular physiology led to the development of antagonists of the Beta-adregnergic receptor, commonly reffered to as beta-blockers. Beta-blockers are one of the most widely used therapeutics for nubmeorus diases including hypertension, coronary artery disease, HF, and arrhythemias. The binding of agonists to receptors was found to be biphasic, showing 2 distinct affinity states (high and low) due to the allosteric effects of G-proteins on the receptors. (Rockman, “G Protein-coupled recetpors: a century of research and discovery” Circulation Research, 2024)

Beta-adrenoceptors (β-ARs) are G protein-coupled receptors (GPCRs). They are a type of cell surface receptor that regulates many cellular processes.

ß-adrenergic receptors are members of a large family of hormone and neurotransmitter receptors that activate membrane-bound enzymes and ion channels through intermediary G proteins. These receptors are integral membrane glycoproteins that are spatially organized as a bundle of seven transmembrane helices. The amino terminus is extracellular and the carboxyl  terminus is intracellular.

–Beta-adrenoceptors (β-AR) in the bladder are responsible for relaxing smooth muscle and increasing bladder compliance during the filling phase of urination. The main subtype of β-AR involved in bladder smooth muscle relaxation is the β3-AR.

Myrbetriq® is a beta-3 agonist that stimulates beta receptors in the bladder, thereby inducing bladder relaxation and imporving bladder function.

Odorant Receptors: are a class of GPCRs, responsible for our sense of smell. Of the 850 genes encoding GPCRs in the human genome, about half are odorant receptors.

Serotonin Receptors:

The monoamine neurotransmitter, 5-Hydroxtryptamine or serotonin, is derived from tryptophan and synthesized both centrally and systemically. Fourteen structurally and functionally distinct receptor subtypes have been identified for serotonin, each of which mediates the neurotransmitter’s effects through a range of downstream signaling molecules and effectors. Although it is most frequently described for its role in the etiology of neuropsychiatric and mood disorders, erotinin has been implicated in a wide range of fundamental physiological processes, including apoptosis, mitochondrial biogenesis, cell proflieration and migration. (Prasad, “The 5-Hydroxytryptamine signaling map: an overview of serotonin-serotonin receptor mediated signaling network” July 2018).

Serotonin acts as a neurotransmitter within the CNS, where it is synthesized by raphe neurons in the brain stem: periopherally it can play multiple roles as a hormone, auto- or paracine factor, and synthesied by both gut neurons and enterochromaffin cells located in the gastrointestinal system. The blood-brin barreir keeps systemic and central serotonin pools distinct. (Prasad, “The 5-Hydroxytryptamine signaling map: an overview of serotonin-serotonin receptor mediated signaling network” July 2018)

The serotonin transproter (SERT) is responsbile for the reuptake of free 5-HT in the synaptic cleft; this is, in fact, the mechanism of action exploited by selective serotnin reuptake inhibitors (SSRIs), typically used as antidepressants or anxiolytic therapy. By blcoking the recapture of 5-HT molecules by SERT, SSRIs increase extracellular 5-HT concentration. (Prasad, “The 5-Hydroxytryptamine signaling map: an overview of serotonin-serotonin receptor mediated signaling network” July 2018)

Taste Receptors:

The taste buds of all terrestrial vetebrates occur in the epithelium of the tongue and oral cavity, within raised areas called papillae. Taste buds are onion shaped structures of between 50-100 taste cells; each cell has fingerlike projections called microvilli that poke through the top of the taste bud, called the taste pore. Within a taste bud, the chemicals that produce salty and sour tastes act directly through ion channels. The prototypical salty taste is due to Na+ ions, which diffuse through Na+ channels into cells receptor cells in the taste bud. Within a taste bud, the chemicals that produce salty and sour tastes act direclty through ion channels. The prototypical salty taste is due to Na ios, which diffuse through Na+ channels into cells in recetpor cells in the taste bud. The Na+ influx depolarizes the membrane, causing the receptor cell to release neurotransmitter and activate a sensory neuron that sends an impulse ot the brain. The cells that detect sour taste act in a similar fashion except that the ion detected is H+. Sour tastes are associated with increased concentration of protons that can also depolarize the membrane when they diffuse through ion channels.

Sweet, bitter, and umami substances bind to G protein coupled receptors specific for each category.

Taste buds are sensory end organs taht are located in the oral epithelium. The receptors on the chemosensitive apical tips of taste bud cells confer specificity to gustatory stimuli. Taste receptors come in many types, including several classes of G protein-coupled receptors (GPCRs) and ion channels. Some stimuli interact with receptors to generate second messengers, whereas in other instances, the taste stimulus itself is transported into the cytoplasm of taste bud cells and activates downstream events. Bitter-taste receptors (T2Rs) are class A GPCRs, and have short N temmini and ligand binding sites in their transmembrane segments. How information from taste buds is transmitted to the CNS and in particular how signals discrimnate sweet, sour, salty, bitter and other tastes are unsettled. One view is the labelled-line coding model, which states that individual taste bud cells exclusively identify a unique taste quality and synapse with different fibres that are dedicated to that quality. Moreover, the entral projections of the afferent neurons are labelled by that same taste quality and synapse with dedicated hindbrian neurons that relay the information for that one quality to higher brain centers, thereby establishing a “labelled line” of transmitted information. (Chaudhari, “Taste buds: cells, signals and synapses” Nat Rev Neurosci, 2017, 18(8), 485-497).