G-protein coupled receptors (GPCRs) comprise a 7 transmembrane-spanning protein family and are the largest and most diverse group of receptors in the human genome. They play an important role in many physiological processes, such as: sensing light, taste and smell, neurotransmitters, metabolism regulators etc. GPCRs are also the target of the most developed drugs. GPCRs signal through multiple transducers (e.g. G- protein and β-arrestin); activating multiple pathways and providing different physiological actions. These pathways can be activated or inhibited by ligands; they can also be selectively activated via biased signalling for more accurate targeting or activation of one pathway over another. Biased signalling is the ability of a ligand to activate a certain signal transduction pathway. The evaluation of biased signalling is very important in the development of drugs. In recent years, many pharmaceutical companies have been developing ligands that have biased signalling ability, to allow for more targeted modulation of cell function and treatment of disease (1,2,3).
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Understanding the mechanisms of biased signalling is very important, since many drugs that target GPCR lack specificity and can, therefore, result in unwanted side effects. An understanding of the mechanisms involved is also important for the understanding of GPCR biology. Biased signalling gives a rise to a cellular response of biochemical reactions, which ensures the efficacy of a ligand required to activate a beneficial pathway, and override the activation of detrimental pathway; leading to a reduction in side effects. The mechanisms of biased signalling are not yet completely understood, but it is known that a biased agonist induces a unique conformational change to GPCRs that will favour one signalling pathway over another (e.g. the G-protein pathway vs the β-arrestin pathway). It is well known that the conformational state stabilized by GPCRs, at which G-protein is activated, is different to the one at which β-arrestin is activated (1,4). For example, a study of the activation of the arginine-vasopressin type 2 receptor (V2R) by biased and unbiased ligands, using a fluorescence-based method, has shown that the transmembrane helix 6- third intracellular loop region of the molecule is associated with the selective activation of a G-protein signalling pathway, while transmembrane helix 7 and 8 region is required for the activation of a β-arrestin pathway (1,4,5).
Biased signalling is induced by biased agonism, biased receptor or a biased system. Biased agonism (also known as ligand bias) is a situation in which a ligand induces a unique receptor conformation that results in differential coupling to the signal transduction cascade and a biased response. It is thought to be caused by stabilisation of distinct receptor conformational states that differentially activate the alternative signalling pathways. Alternatively, biased receptor is generated by modifying the receptor to change its binding ability with specific ligands. Biased receptors can occur through mutation or differential splicing; both causes can alter coupling to G-protein and β-arrestin. However, a biased system can be controlled by differential expression of transducer elements proximal to the receptor, for example β-arrestin - the receptor or GRK. Therefore, due to a biased system, it is difficult to predict the true signalling bias (5,6,7). Most pharmacological GPCR agonists target orthosteric binding sites, but recent experiments have identified multiple agonists that can target allosteric, or topographically distinct, binding sites on the receptors (6).
Favouring a G-protein signalling pathway, through biased signalling, is mostly observed in a μ-opioid receptor. It has been observed that there is a restriction in the expression of G-protein subunits in some tissues, which prevents some combinations from forming. Due to this restriction, there is the potential of cell-based biased signalling. This type of signalling bias might be important in drug therapy, due to differential activation of G-protein subunits that have shown some clinical benefits (8). For biased signalling to favour the β-arrestin pathway, it will enhance the phosphorylation of GPCRs by G protein receptor kinases (GRKs) and desensitize G-protein signalling pathways. Biased signalling via β-arrestin is very complex, since it has many consequential actions in the cell and also because there are many therapeutically activate pathways that can be explored. It is suggested that signalling mediated via β-arrestin has many beneficial outcomes, via many GPCRs, such as; promoting antipsychotic dopamine D2 receptor activity, and increasing cardio protection via the angiotensin II receptor. Some experiments have shown that biased signalling, via biased agonism, has the ability to recruit many different subtypes of β-arrestin within a signal receptor (9).
The discovery of new drugs that only target the primary ligand binding sites of GPCRs is becoming more and more difficult, because many of the developed and in development ligands that target GPCRs lack specify for a certain pathway and the interaction between ligand and GPCRs that results in receptor confirmation for a certain pathway is not fully understood. But, the promise of new therapeutic potential is brought by the production of biased signalling via a ligand. Also, biased signalling brings a challenge to the process of drug discovery, because the understanding of physiological responses which are due to G protein versus arrestin interactions is clearly known. So, in order to develop new drugs that act as biased ligand/agonists, a clear understanding of the physiological effects of biased signalling is required. Since biased agonism is expected to have different functional and physiological effects, as agonists only activate a selected pathway, it will also inhibit others. So, in order to develop ligands that produce a biased signalling effect for a specific pathway there must be evidence that the pathway that is being targeted will bring a clinically useful effect (10,11).
An example of how biased signalling is used in developing novel therapeutics is the discovery of μ-opioid receptor agonists that show a pain management effect. This shows that they mediate their analgesic effect via a G-protein signalling pathway, while the side effects are mediated by a β-arrestin signalling pathway. Biased agonism of μ-opioid receptors will act as an agonist through G-protein signalling pathway, while acting as an antagonist through the β-arrestin signalling pathway. Olicaeriden is one agent that shows this characteristic and has now reached the late stages of clinical development, with many more drugs of this nature being currently under preclinical development (12,13). Other drugs that induce biased signalling through G-protein pathways, are MCF14/18/57. They act as the agonist through G-protein mediated pathway, but as antagonist through β-arrestin mediated pathway. This reveals that the drug is shown to have many beneficial benefits in treating many renal diseases (14).
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Carvedilol, another example, is a drug used in treatment of cardiovascular diseases. It is a β-adrenergic receptor antagonist and has the capacity to act as an agonist through the β-arrestin mediated pathway, while acting as the antagonist through a G-protein mediated pathway. It is a very effective treatment for heart failure. In addition to Carvedilol, a drug called TRV120027 which acts at the angiotensin II type 1 receptor, behaves in the same way as Carvedilol; being a β-arrestin biased ligand, it shows that causes a beneficial cardiorenal outcome, such as increasing survival rate of cardiomyocyte (15). Recent studies have found that Fenoterol a drug used to treat asthma induces biased signalling, through its action on the β2 adrenoreceptor. It acts, as an agonist on the G-protein signalling pathway while it acts as an antagonist on the β-arrestin pathway. These studies suggest that identifying ligand that only activates G-protein signalling pathways of β2-adrenoreceptor can provide a new therapy for treating asthma with a maintained efficacy by switching off the β-arrestin singling pathway. (16,17,18)
Despite current headway in the field of biased signalling, further studies are required to understand how the interaction between GPCRs, and ligands is translated into the receptor conformation state for a selected pathway (e.g. G-protein vs β-arrestin pathway). Also, a wider understanding of biased signalling via an agonist at the pharmacological and physiological level is required, in order to make progress in terms of developing new and promising, novel therapeutics. Such progress would move drug development process much closer to production of biased drugs that only activate a particular signalling pathway, with fewer side effects. Also, more research is required for further understanding of the roles of G-protein and β-arrestin signalling pathways in health and disease. Therefore, future studies should not only focus on developing new ligand with biased signalling but also focus on the physiological effect of these two signalling pathways. Also, biased signalling can be very important further the understanding cells intracellular signalling pathways.
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