Progress in GPCR Signaling Pathway and Its Drug Research

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Mar 08, 2019

GPCR molecular structure

GPCR molecules have a conserved structure and are widely expressed in various tissues. Recently, nearly 1000 different GPCRs have been discovered by humans, and each binds to a specific signal.

GPCRs consist of a single polypeptide that can be folded into a globular shape and embedded in the plasma membrane of the cell, the diversity of which is mainly caused by the coding of seven transmembrane domain (TMD) sequences. TMD forms the receptor core shared by all GPCRs. According to the evolutionary conservation of these sequences, GPCRs are divided into multiple subfamilies, such as rhodopsin-like, secretin receptor-like, and biological receptors, class C (metabotropic glutamate receptor-like), class F (frizzled-like) and taste 2 sensory receptor subfamily.

GPCR diversity
GPCR diversity allows for a variety of functions, including alternative splicing, RNA editing, post-translational modification, and protein-protein interactions. The diversity of GPCRs also allows these receptors to recognize and respond to a wide variety of ligands such as light energy, compounds, ions, neurotransmitters, neuromodulators, hormones, glycoproteins, and other proteins.
In the GPCR signaling pathway, the receptor needs to be signalled after binding to the heterotrimeric G protein.
The G protein is composed of three subunits of Gα, Gβ and Gγ. In the human body, there are 16 Gα, 5 Gβ and 13 Gγ subunit combinations, forming various patterns of heterotrimeric G protein. Each Gα subunit can serve as a separate conduction signal, and the Gβ subunit and the Gγ subunit must bind together to form a Gβγ unit. The 16 Gα subunits can be divided into four major Gα families (Gs, Gi/o, Gq/11, and G12/13), which regulate key effectors (adenylate cyclase, phospholipase C, etc.) and The generation of two messengers (cAMP, Ca2+, inositol 1,4,5-triphosphate, etc.) activates different cascades of signals. Different receptors have been shown to be coupled to the same Gα subunit, and the same receptor can be coupled to a variety of Gα subunits. The Gβγ subunit has regulatory and signaling functions, such as regulators of receptor kinases and ion channels.

Complexity of GPCR signaling pathway
GPCRs act as variable conformation proteins that allow information to be transferred from outside the cell to the inside. These receptors also have multiple conformations in the absence of activating ligands. Endogenous ligands and drugs can alter the conformation of the receptor, causing downstream signaling. GPCRs activate proteins that require activation and can be coupled to a variety of transduction and regulatory proteins.
In addition, for some receptors, including the viral chemokine receptor GPCR homologue US28, dopamine receptor and serotonin receptor 2C (5HT2C), it can usually be regulated by overexpression or mutation of GPCR. The constitutive activity level of the receptor is related to its conformation and is also regulated by the interaction between the transmembrane core amino acids, particularly the interaction between the conserved polar amino acids. The activity of GPCRs is also regulated by intrinsic mechanisms, such as receptors that reach the cell surface via chaperones, or receptors that circulate on the membrane by endocytosis.

GPCR signal control site
GPCR signaling through membrane lipid interactions and changes in lipid composition and receptor recruitment to "lateral" allogeneic proteins in protein signalsome complexes that limit or alter the interaction of effectors and modulators with receptors Role, thereby changing the signal transmission effect.
The plasma membrane is a key environment for signal transduction and has a complex structure with up to 1000 different types of lipids. These lipids can interact directly with the receptor, or they can form "microdomains" by interaction with membrane proteins, affecting the conformational dynamics of GPCR. GPCRs can be dynamically allocated between these "microdomains", resulting in changes in signaling.
GPCR receptor transport is regulated by dynamic cycling and dependent interactions in different cells. Down-regulation of receptor responses is achieved by targeted degradation of receptors, and receptors are controlled by post-translational modifications (eg, phosphorylation, ubiquitination). Transportation efficiency.
GPCRs assemble with other proteins into multiprotein complexes that alter receptor function and cellular responses. The heteromeric assembly of the receptor can alter receptor trafficking in response to physiological ligands. GPCRs can also interact with non-GPCR ligands, altering ligand recognition, participating in transducer activation, or receptor trafficking. GPCRs can also interact with membrane proteins such as RAMP, MRAP and LRP. Assembling a GPCR into a signal body provides a very fine signaling pathway for the cell.

GPCR drugs and clinical research drug classification
Currently, FDA-approved GPCR-targeted drugs total 475, accounting for 34% of all FDA-approved drugs. There are 321 targeted GPCRs in the study period, of which 60 (19%) are targeted by innovative GPCR targets.
In this review article, the researchers believe that the existing GPCR targets have become saturated, targeting a total of 108 GPCR targets in approved GPCR drugs. In the GPCR drug targets that have been identified, each target can be targeted by 10.3 different drugs, indicating that the space of these targets is near saturation, and the development of new drugs requires the discovery of more new receptors, especially for those For diseases with huge medical needs and relatively lack of targets, it is worthwhile to study new targets (such as Alzheimer's disease).
The researchers found through data analysis that polypeptide or protein-activated GPCRs are more concerned. Of the 66 innovative GPCR targets in the clinical trials, 37 are polypeptide or protein-activated GPCRs, and 22 are drug-targeting tropism receptors, which include cancer, asthma, and rheumatoid joints. A variety of diseases such as inflammation and AIDS. These new targets are widely distributed across GPCRs in different classes and families, demonstrating new R&D strategies to help identify innovative targets.

Trends in targeting GPCR drug indications
Researchers have found that indications for targeting GPCR drugs have evolved from traditional areas of hypertension, allergies, anesthesia and schizophrenia to new areas of AD and obesity. Of course, central nervous system diseases remain an important part of targeting GPCR drug indications. Of the approved GPCR-targeted drugs, 26% of drugs treat central nervous system diseases, and at least 79 clinically-targeted GPCR-targeted drugs are used to treat central nervous system diseases. Among them, MS, AD, Huntington's disease and fragile X chromosome syndrome are particularly worthy of attention.
The increase in the market share of drugs for the treatment of metabolic diseases is also reflected in the clinical trials of targeted GPCRs, of which 27 are in the treatment of diabetes and 7 are in the treatment of obesity. As mentioned earlier, peptide drugs targeting the GLP1 receptor have been marketed, but currently approved are injectable drugs. Oral-targeted peptides targeting GLP1 receptors and small molecule drugs are in clinical phase 2 and phase 3 trials.
In the treatment of diabetes and its complications, there are currently 25 new GPCR targets that are tested in clinical trials. Among the new targets to be noted are GPR119, FFA1 receptor and dopamine D2 receptor.
There are currently 21 anticancer drugs targeting 14 different GPCRs, including GnRH receptor antagonists and SMO receptor inhibitors. In clinical trials, 23 in-situ drugs targeting GPCRs are used to treat cancer, and 7 of them target innovative targets. These innovative targets include chemokine receptors and proteins in the WNT signaling pathway, such as CCR2, FZD7.

In the future, more new GPCR targets will be discovered, such as CaS receptor, glycoprotein hormone receptor and Frizzled receptor, as well as some orphan receptors such as GPR84, GPR1, GPR17, LGR5 and so on. With the analysis of the crystal structure of the GPCR, more drugs can be developed.
In this paper, the bias-activated specific signaling pathway becomes a new mechanism of functional specificity. GPCRs can activate multiple signaling pathways, and activation of appropriate signaling pathways is important for obtaining beneficial cellular responses and physiological responses. Recent studies have shown that some molecules can preferentially activate specific signaling pathways, which provides a new mechanism to reduce side effects. Research into the medical applications of drugs that have a propensity to activate specific signaling pathways is just beginning, and we need a more complete understanding of the GPCR signaling pathway.

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