GPCR

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.

GPCRs 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.

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.

Adapted from Maggio et al., 2023

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.