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== G-Protein Coupled Receptors ==

[https://proteopedia.org/wiki/index.php/G_protein-coupled_receptors G-protein coupled receptors](GCPRs) are a large family of cell surface membrane receptors. Once bound to a wide variety of extracellular ligands, GCPRs undergo a conformational change and relay information to intracellular secondary messengers <ref name="Thal">Thal, David M., et al. "Structural insights into G-protein-coupled receptor allostery." Nature, Nature Publishing Group, 04 July 2018, https://www.nature.com/articles/s41586-018-0259-z</ref>. This G protein activation results in a cellular response dependent on the ligand bound and location of the GPCR in the body. GCPRs can be broken down into five families: the [https://en.wikipedia.org/wiki/Rhodopsin-like_receptors rhodopsin family (class A)], the [https://en.wikipedia.org/wiki/Secretin_receptor_family secretin family (class B)], the [https://en.wikipedia.org/wiki/Adhesion_G_protein-coupled_receptor adhesion family], the [https://en.wikipedia.org/wiki/Class_C_GPCR glutamate family (class C)], and the [https://en.wikipedia.org/wiki/Frizzled frizzled/taste family (class F)] <ref name="Zhang">PMID: 26467290</ref>. All of the families have a similar transmembrane (TM) domain consisting of <scene name='90/904328/7tm_domain_pt_3/7'>seven α-helices</scene> complexed with intracellular G proteins (Figure 1).

=== 2. MRGPRX2 interaction with G-Protein ===

[[Image:Gq_and_Gi_snip.PNG|300px|right|thumb|'''Figure 4''': Caption.<ref name="Cao"/>]]

Once the ligand is bound, MRGPRX2 undergoes a conformational change that is transmitted through to the [https://en.wikipedia.org/wiki/G_protein#:~:text=G%20proteins%2C%20also%20known%20as,a%20cell%20to%20its%20interior. G-protein]. This conformational change is affected by the aforementioned deviances from Class A GPCRs. Rather than a large conformational change, a subtle one is induced. This will allow MRGPRX2 to interact with a G-protein. G-proteins are composed of 3 subunits; α, β, and γ. When activated, the receptor acts as a Guanine nucleotide factor (GEF) which will allow the Gα subunit to have its GDP be replaced by a GTP. This will cause the Gα subunit to dissociate from the dimer Gβγ. The Gα subunit is then able to act as a secondary messenger to begin the signal transduction in the cell. MRGPRX2 interacts with two different types of G-proteins; Gi and Gq. These G-proteins are activated by similar interactions with the receptor however, they are structurally different and changes in the induced conformation are observed (Figure 6). Due to these structural differences, differences in ligand binding to MRGPRX2 bound to Gi in comparison to Gq are observed (Figure 5).   

MRGPRX2 also interacts with Gi or G-protein inhibitory, which is structurally homologous to Gs (G-protein stimulatory), and will inhibit adenylyl cyclase and therefore lowers (cAMP). Gi is stimulated when somatostatin binds to receptor in pancreas.

== Clinical Relevance ==

This receptor is shallow and is able to bind to a variety of drugs, creating a need a solution to mediate the effects of MRGPRX2 activation. Currently, there is research for the development of small antagonists that will induce an anti-inflammatory effect by prevent [https://en.wikipedia.org/wiki/Immunoglobulin_E IgE-dependent] mast cell degranulation.<ref name="McNeil">McNeil, B. D., et al. "MRGPRX2 and Adverse Drug Reactions." Frontier Immunology, 06 August 2021, https://www.frontiersin.org/articles/10.3389/fimmu.2021.676354/full</ref> There are two antagonists that have been adapted from being agonists to another Class A GPCR, [https://en.wikipedia.org/wiki/NK1_receptor_antagonist neurokinin-1 receptor (NK-1R)].<ref name="Ogasawara">Ogasawara, H., et al. "Novel MRGPRX2 antagonists inhibit IgE-independent activation of human umbilical cord blood-derived mast cells." Journal of Leukocyte Biology, 12 July 2019, https://jlb.onlinelibrary.wiley.com/doi/10.1002/JLB.2AB1018-405R</ref> Through the development of this research, these adverse side effects can be relieved and improve patient satisfaction.

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== References ==

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