GPCRs & Their heteromers
G protein-coupled receptors (GPCRs), which represent the largest membrane protein family, are cell surface receptors that transmit extracellular stimuli to intracellular signaling. GPCRs activate intracellular signal pathways through their associated G proteins. They recognize various ligands such as hormones, neurotransmitters, inflammatory mediators, nucleic acids, peptides, amino acids, lipids, and light.
Nearly 800 GPCRs have been identified in humans so far. Many GPCRs contain mutations or polymorphisms that are associated with a variety of diseases and disorders. Nearly 40% of all marketed drugs are known to act through GPCRs and more than 30% of the new drugs in development are targeting GPCRs. Despite the fact that GPCRs form the largest superfamily of cell surface receptors involved in signal transmission, in clinical practice only few anticancer compounds are currently used in order to interfere with GPCR-mediated signaling. GPCRs control many aspects of cancer progression including tumor growth, invasion, migration, survival and metastasis supporting the importance of blockade of this pathway.
Since the mid-1990s, it has been reported that a variety of GPCRs form heteromers. Heteromerization is now accepted as a general characteristic of GPCRs. Heteromerization of GPCRs has been shown to result in altered biological responses through regulating ligand affinity, signaling intensity, receptor trafficking, or changing signal pathways.
The diversity of GPCR heteromerizations and their mode of action represents an unprecedented challenge and opportunity to discover novel drug targets and develop new therapeutics with higher selectivity and reduced toxicity.