Did you know that G protein-coupled receptors (GPCR) comprise approximately 800 genes, corresponding to 2% of the human genome? G protein-coupled receptors are transmembrane domain receptor proteins and are responsible for allowing communication between cells, such as when motor neurons release a chemical message picked up by a muscle fiber that signals the muscle fiber to contract, allowing the muscles in the human body to move. GPCRs demonstrate an impressive ability to mediate responses to neurotransmitters (chemical messengers utilized by the nervous system to communicate messages between neurons) and hormones (chemical substances that circulate in the bloodstream and regulate the actions of certain cells and organs), as the attachment of specific ligands to the GPCR activates physiological responses in organisms—for example, GPCR binds epinephrine, a crucial substance for fight or flight situations. Furthermore, nearly half of all medications accomplish their task of inhibiting the hormones specific to them through the work of GPCRs. Thus, GPCRs are extremely important in ensuring that cellular activities occur at the correct time, in the correct cell, and in proper coordination with the activities of other cells.
During the 1980s, researchers Brian Kobilka and Robert Lefkowitz made a substantial discovery in the inner workings of these spectacular transmembrane proteins. Kobilka and Lefkowitz discovered that GPCRs resemble the receptor protein in the human eye that captures light and that there is a whole family of receptors that resemble one another. Thus, due to their similar structures, these receptors perform very similar functions. G protein-coupled receptors have a lot of potential for being high-priority candidates for medical research that can be used to treat genetic illnesses.
With further research into their function, G protein-coupled receptors have extreme value for treating genetic diseases. Numerous drugs, such as epinephrine, are substances that imitate hormones or neurotransmitters when they bind to particular receptors in the brain. Agonists will agonize or stimulate a GPCR to start its signaling inside the cell and produce a specific biological response in the signal transduction phase of a signaling pathway where the GPCR converts the chemical message contained in the signaling molecule to a “decoded” form that brings about the transmission of a particular response in the cell. The response could be something along the lines of cell growth and immune responses. Through the sequence of events from the activation of a GPCR by a first messenger, which in turn subsequently activates a G protein, leading to cellular response within the cell, GPCRs possess the ability to regulate growth, sensation, hormonal regulation, and neuronal activity in organisms.
In this graph derived from the National Library of Medicine, “G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs,” by Krishna Sriram and Paul A. Insel, we see the number of GPCRs targeted by approved drugs from various ligand activity charts including ChEMBL and GtoPdb. Notably, FDA-approved drugs target 134 GPCRs. Currently, available drugs that target a GPCR include opioid agonists, signaling molecules that activate opioid receptors in the peripheral and central nervous systems. Before recent research in cellular communications, GPCRs were normally thought to only be coupled to one G protein, meaning that they bind agonists to the activation of a G protein. However, individual GPCRs can be coupled to multiple different G proteins, with different timing, enabling the GPCRs to stimulate different signaling cascades in waves, therefore transmitting important biochemical information between a cell’s nucleus and its plasma membrane. However, issues can occur due to mutations in a G protein-coupled receptor, resulting in inherited or acquired diseases. Per the Pharmacological Reviews article, “Mutations in G Protein-Coupled Receptors: Mechanisms, Pathophysiology, and Potential Therapeutic Approaches,” by Ines Liebscher and Torsten Schöneberg, there are more than 2,350 mutations in 55 GPCR genes, linked to 66 human diseases.
Different diseases can stem from a single GPCR gene, and most genomic alterations are from splice-site mutations (3%), nonsense mutations (7%), small inserts/deletions (16%), gross deletions/rearrangements (6%), and predominantly from missense mutations (68%). If the scientific community tries to optimize GPCR proteins to assay the concentration effect of a whole agonist over a range of cell densities, then we can continue to examine its effectiveness in helping to treat genetic illnesses. Many genetic variations in G protein-coupled receptor genes disrupt the function of the GPCR, causing several human genetic diseases. Therefore, further research into GPCRS can be used to treat genetic illnesses resulting from mutations in the GPCR, including retinitis pigmentosa and nephrogenic diabetes insipidus.
Current research into optimizing GPCR proteins for their clinical application is being conducted. In the PubMed article, “Optimization of Recombinant GPCR Proteins for Biophysical and Structural Studies Using Virus-like Particles,” by researchers Kathleen Aertgeerts, Thao T. Ho, and Yingzhou G. Yan, it is said that the implementations of iterative optimization cycles involving protein purification, engineering, and expression are needed to obtain ideal protein quality and quantity and are currently utilizing restoration of GPCRs in virus-like particles and their usage in biophysical assays to characterize protein stability and yield.
Consequently, GPCRs play a crucial role in ensuring that cells effectively and efficiently communicate with one another, thereby allowing the transmission of important cellular responses, such as the binding of epinephrine in or allowing neurons to deliver chemical messages to muscle cells. With current research into optimizing GPCRs so that they can be used, clinically speaking, to treat genetic illnesses, the scientific community will have a greater knowledge on the true value and versatility in function of a GPCR, and perhaps, that of other transmembrane domain receptor proteins such as receptor-tyrosine kinases (RTKs) and ligand-gated ion channels.
