G protein-coupled receptors (GPCRs) constitute the largest superfamily of human cell surface transmembrane receptors with over 820 genes. They respond to a variety of ligands that include hormones, neurotransmitters, metabolites, ions, photons, and mechanical forces, with subsequent intracellular signaling relayed through G protein-dependent and -independent mechanisms. GPCR-triggered pathways are responsible for a plethora of physiological and pathophysiological effects, which is why approximately a third of all prescribed drugs target their activity. Of the more than 350 human GPCRs that are not sensory receptors, perhaps 140 are considered “orphan” receptors with no known ligand or function. Emphasizing their clinical value, it is thought that ~60-85% of potentially therapeutic GPCRs have no drugs directed at them. 

 

Physiological Functions of GPCRs

GPCRs play a crucial role in the regulation of tissue/cell physiology and homeostasis in the immune, nervous, endocrine, and cardiovascular systems, among others. They also function in a multitude of pathological processes, including cancer.

 

 

GPCRs in cancers

Many GPCRs serve as potential biomarkers for early cancer diagnosis. Furthermore, GPCRs are active in various aspects of cancer progression, including proliferation, apoptosis, angiogenesis, migration, and invasion. Therefore, the pharmacological inhibition of GPCRs and their downstream targets presents a promising avenue for developing novel, mechanism-based strategies for cancer therapy.

 

GPCRs in the immune system

Inflammatory cells such as leukocytes, monocytes, macrophages, and dendritic cells express more than one GPCR and sense a wide range of chemoattractants and chemokines. These receptors are crucial for the migration and infiltration of immune cells. Abnormal GPCR expression can lead to immune system dysfunction manifesting as inflammatory and autoimmune disease.

 

GPCRs in the nervous system

The nervous system utilizes membrane receptors to detect extracellular stimuli. By expressing GPCRs with diverse ligand-recognition capabilities, the nervous system can selectively filter and respond to specific signals. GPCRs are involved in chronic neurodegenerative diseases including but not limited to Alzheimer's disease, Huntington's disease, and Parkinson's disease.

 

GGPCRs in homeostasis

GPCRs play a crucial role in maintaining metabolic balance by influencing key processes such as glucose homeostasis and insulin secretion, appetite, calcium sensing, heart rate, and blood pressure.

 

 

Table 1. GPCRs related to different disorders

 

 

Disorder GPCRs Cancer Bradykinin receptor Chemokine receptors Endothelin receptors Frizzled receptors Protease-activated receptors Prostaglandin receptors Immunological disorders Adenosine recepto Anaphylatoxin receptors (C3aR, C5aR, and C5L2) Cannabinoid receptors Chemokine receptors Histamine receptors Neurokinin receptors Prostaglandin receptors Protease-activated receptors

 

 

 

CXCR1 antibody [HL2674] GTX639338	CXCR2 antibody [HL2604] GTX639056	CXCR4 antibody [HL2424] GTX638646	Adenosine A1 Receptor antibody [HL2442]  GTX638758

 

FPRL1 antibody [HL2664] GTX639328

 

 

 

Disorder GPCRs Neurodegenerative diseases Alzheimer's disease Adenosine A2A receptor Adrenergic receptors Corticotrophin-releasing hormone receptors Metabotropic glutamate receptors Serotonin receptors delta-opioid receptor Parkinson's disease Adenosine A2A receptor Adrenergic receptors Metabotropic glutamate receptors serotonin receptor Huntington's disease Cannabinoid receptors Metabotropic glutamate receptors

 

Dopamine Receptor D2 antibody [HL1478] GTX636952	Somatostatin receptor 3 antibody [HL2681] GTX639345	Dopamine Receptor D1 antibody [HL2680] GTX639344

 

 

 

Disorder GPCRs Metabolic disorders Obesity Bile acid receptor Melanocortin receptors Type 2 diabetes Free fatty acid-binding receptors Glucagon receptors Incretin receptors ( GLP1R and GIPR) Somatostatin receptors Cardiovascular diseases Adenosine receptors Angiotensin II receptors

 

GLP1R antibody [HL2297] GTX638352	AGTR1 antibody [HL2524] GTX638885

 

GPCR Classification and Structure

GPCRs share structural characteristics that include seven transmembrane (7TM) domains linked by both intra- and extracellular loops, an extracellular N-terminus, and an intracellular C-terminus. The loops, as well as the intra- and extracellular domains, are all subject to post-translational modifications. One widely used GPCR classification system is based on sequence homology and evolutionary relationships. This organizes GPCRs into six families designated A-F.

 

 

 

Table 2. GPCR families

Family Class General Structure (Adapted from Qu et al., 2020) Ligand Interaction (Adapted from Xu et al., 2024) Class A Rhodopsin-like (R)   Class A (Rhodopsin-like) GPCRs account for more than 85% of human GPCRs. This class is distinguished structurally by an additional palmitoylated 8th alpha helix.

Class A

Rhodopsin antibody [HL2668] GTX639332	Rhodopsin antibody [HL2668] GTX639332	CCR4 antibody [HL2492] GTX638850

 

 

Family Class  General Structure (Adapted from Qu et al., 2020) Ligand Interaction (Adapted from Xu et al., 2024) Class B1 Secretin (S)   Class B1 (Secretin) GPCRs are characterized by their large extracellular domains (ECDs) that are able to bind large peptidic ligands such as hormones or neuropeptides. Class B2 Adhesion (A)   Similar to Class B1, Class B2 (Adhesion) GPCRs feature a large ECD. Signaling results from the pre-digestion of the GPCR autoproteolysis-inducing (GAIN) domain at the GPCR proteolytic site (GPS) motif. Mechanical force releases the Stachel peptide that then acts as a tethered agonist to bring about 7TM activation.   The individual N-terminal motifs of the subgroups reflect their unique roles in cell adhesion and migration.

 

 

Class B1

GLP1R antibody [HL2297] GTX638352	GLP1R antibody [HL2297] GTX638352

 

Class B2

CD97 antibody [HL1925] GTX637674	CD97 antibody [HL1925] GTX637674

 

 

Family Class  General Structure (Adapted from Qu et al., 2020) Ligand Interaction (Adapted from Xu et al., 2024) Class C Glutamate (G)   Class C (Glutamate) GPCRs are distinctive for large ECDs, which include a Venus Fly Trap (VFT) domain and a cysteine-rich domain (CRD), and their mandatory homo- or heterodimerization. Class F Frizzled (F)   Class F (Frizzled) GPCRs feature a cysteine-rich domain (CRD) and a linker domain (LD) in the ECD. Members of this class play roles in development and regeneration through activation of the downstream Wnt or Hh signaling transduction pathways.

 

Class C

 

 

Calcium Sensing Receptor antibody [HL2357] GTX638563	Calcium Sensing Receptor antibody [HL2357] GTX638563

 

Class F

Frizzled 9 antibody [HL1675] GTX637274	Frizzled 9 antibody [HL1675] GTX637274

 

Regulation of GPCR Signaling

GPCR signaling begins with engagement of the receptor by a ligand, which leads to allosteric changes in the intracellular domains of the GPCR. In general, two types of effectors can then associate with the GPCR: (a) a Gα subunit that complexes with β and γ subunits to form the G protein trimer, and (b) β-arrestins that can direct their own signaling. It is becoming clear that GPCR signaling emanates not only from the cell surface but also from other intracellular compartments (e.g., endosomes, the Golgi apparatus, and the ER, among others). Signaling cascades involving kinases and transcription factor regulation orchestrate the subsequent cellular response.

 

Classically, GPCR signaling undergoes termination through GTP hydrolysis and dissociation of Gα-Gβγ. G protein-coupled receptor kinases (GRKs) phosphorylate the C-terminal tail of GPCRs, facilitating the binding of the β-arrestins that, as mentioned above, can trigger their own signaling as well as contribute to GPCR desensitization and internalization. The GRK family, comprising seven kinases (GRK1-7), is categorized into three subfamilies: (1) the GRK1 subfamily consists of rhodopsin kinase (GRK1) and GRK7, (2) the GRK2 subfamily consists of β-adrenergic receptor kinase-1 and -2 (GRK2 and GRK3), and (3) the GRK4 subfamily consists of GRK4-6. GRK2, GRK3, GRK5, and GRK6 are key regulators of GPCRs. Beyond GRKs and arrestins, GPCR functions and signal transduction are influenced by GPCR-interacting proteins (GIPs) such as receptor activity-modifying proteins (RAMPS), regulators of G protein signaling (RGS) proteins, GPCR-associated sorting proteins (GASPs), Homer proteins, and PDZ-scaffold proteins.

 

 

Protein High-expressing tissues GRK2 Bone marrow, spleen, lymph node, tonsil, and thymus GRK3 Adipose tissue, spleen, cerebral cortex, tonsil, and hippocampus GRK5 Heart muscle, lymph node, parathyroid gland, placenta, and gallbladder GRK6 Bone marrow, lymph node, spleen, thymus, and granulocytes β-arrestin1 Monocytes, cerebral cortex, pancreas, amygdala, and spleen β-arrestin2 Bone marrow, spleen, granulocytes, liver, and monocytes

 

Adapted from Chen et al., 2021 and Shukla et al., 2013

 

Adapted from Cheng et al., 2023

 

 

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