User:R. Jeremy Johnson/GPR40: Difference between revisions
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== Background == | == Background == | ||
Human G-protein coupled receptor 40 (hGPR40), also known as free fatty acid 1 receptor (FFAR1), is a seven helical transmembrane domain receptor for long-chain free [https://en.wikipedia.org/wiki/Fatty_acid fatty acids] that induces insulin secretion.<ref name="Srivastava">PMID:25043059</ref> Some known fatty acid substrates of hGPR40 include [http://www.news-medical.net/health/What-is-Linoleic-Acid.aspx linoleic acid], [http://www.livestrong.com/article/438717-what-is-oleic-acid/ oleic acid], [http://www.hmdb.ca/metabolites/hmdb02925 eicosatrienoic acid], and [https://en.wikipedia.org/wiki/Palmitoleic_acid palmitoleic acid]<ref name="Morgan">PMID:19660440</ref>. hGPR40 is highly expressed in human pancreatic [https://en.wikipedia.org/wiki/Beta_cell β cells], brain, and endocrine cells of the [https://en.wikipedia.org/wiki/Gastrointestinal_tract gastrointestinal tract].<ref name= | Human G-protein coupled receptor 40 (hGPR40), also known as free fatty acid 1 receptor (FFAR1), is a seven helical transmembrane domain receptor for long-chain free [https://en.wikipedia.org/wiki/Fatty_acid fatty acids] that induces insulin secretion.<ref name="Srivastava">PMID:25043059</ref> Some known fatty acid substrates of hGPR40 include [http://www.news-medical.net/health/What-is-Linoleic-Acid.aspx linoleic acid], [http://www.livestrong.com/article/438717-what-is-oleic-acid/ oleic acid], [http://www.hmdb.ca/metabolites/hmdb02925 eicosatrienoic acid], and [https://en.wikipedia.org/wiki/Palmitoleic_acid palmitoleic acid]<ref name="Morgan">PMID:19660440</ref>. hGPR40 is highly expressed in human pancreatic [https://en.wikipedia.org/wiki/Beta_cell β cells], brain, and endocrine cells of the [https://en.wikipedia.org/wiki/Gastrointestinal_tract gastrointestinal tract].<ref name=”RenXM”>PMID:26974599</ref> hGPR40 is of particular interest because the triggering of insulin secrection is [https://en.wikipedia.org/wiki/Glucose glucose] dependent.This glucose-dependence for hGPR40 signaling makes it a target for the treatment of [https://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 type-2 diabetes] as agonists could increase glycemic control and lower the risk of hypoglycemia.<ref name="Srivastava"/> GPR40 is a member of a group of homologous [[GPCRs]] all located on chromosome 19q13.1 including GPCR41, 42, and 43.<ref name="Burant">PMID:23882043</ref> Evidence exists that shows GPCR43 is involved in adipogenesis. | ||
== Function == | == Function == | ||
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=== Binding Sites === | === Binding Sites === | ||
GPR40’s natural substrate are FFAs in which a free [https://en.wikipedia.org/wiki/Carboxylic_acid carboxyl group] is required to bind. However, GPR40 can be activated by a wide variety of fatty acids with chain lengths ranging from [https://en.wikipedia.org/wiki/Saturated_fat saturated fatty acids] with 8 carbons to 23 carbons. In addition, various [https://en.wikipedia.org/wiki/Monounsaturated_fat mono] (i.e. [https://en.wikipedia.org/wiki/Palmitoleic_acid palmitoleic] (C16:1) and [https://en.wikipedia.org/wiki/Oleic_acid oleic] (C18:1) acids) and [https://en.wikipedia.org/wiki/Polyunsaturated_fatty_acid poly-unsaturated fatty acids] (i.e.[https://en.wikipedia.org/wiki/Linoleic_acid linoleic] (C18:2) and [https://en.wikipedia.org/wiki/List_of_unsaturated_fatty_acids#Eicosatrienoic_acid eicosatrienoic] (C20:3) acids) can activate GPR40.<ref name="Morgan"/> The agonists potency varies according to the carbon-chain length however. The activity of GPR40 increases when the chain is increased from C6 to C15 but then decreased when the chain was extended beyond C15. One explanation for this is that as [https://en.wikipedia.org/wiki/Alkyl alkyl] chain increased, so did the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] interactions with the protein within the binding pocket. However, for FFAs with carbon chains longer than C15, the molecular size is too large for the binding pocket. This causes the alkyl chain to extend beyond the binding pocket and destabilize the binding.<ref name= | GPR40’s natural substrate are FFAs in which a free [https://en.wikipedia.org/wiki/Carboxylic_acid carboxyl group] is required to bind. However, GPR40 can be activated by a wide variety of fatty acids with chain lengths ranging from [https://en.wikipedia.org/wiki/Saturated_fat saturated fatty acids] with 8 carbons to 23 carbons. In addition, various [https://en.wikipedia.org/wiki/Monounsaturated_fat mono] (i.e. [https://en.wikipedia.org/wiki/Palmitoleic_acid palmitoleic] (C16:1) and [https://en.wikipedia.org/wiki/Oleic_acid oleic] (C18:1) acids) and [https://en.wikipedia.org/wiki/Polyunsaturated_fatty_acid poly-unsaturated fatty acids] (i.e.[https://en.wikipedia.org/wiki/Linoleic_acid linoleic] (C18:2) and [https://en.wikipedia.org/wiki/List_of_unsaturated_fatty_acids#Eicosatrienoic_acid eicosatrienoic] (C20:3) acids) can activate GPR40.<ref name="Morgan"/> The agonists potency varies according to the carbon-chain length however. The activity of GPR40 increases when the chain is increased from C6 to C15 but then decreased when the chain was extended beyond C15. One explanation for this is that as [https://en.wikipedia.org/wiki/Alkyl alkyl] chain increased, so did the [https://en.wikipedia.org/wiki/Hydrophobe hydrophobic] interactions with the protein within the binding pocket. However, for FFAs with carbon chains longer than C15, the molecular size is too large for the binding pocket. This causes the alkyl chain to extend beyond the binding pocket and destabilize the binding.<ref name="RenXM" /> | ||
FFAs bind to hGPR40 by coordinating its free carboxyl group to three amino acids, <scene name='72/727085/Ffa_binding/1'>Arg183, Tyr2240, and Arg258</scene>, which are located close to the <scene name='72/727085/Hgpr40_transmane_active/1'>extracellular domain</scene> of hGPR40 on TM5, 6 and 7. Because of the close proximity of these residues to the extracellular domain and the dominantly hydrophobic nature of FFA’s, it is likely that ligand binding occurs close to the plane of the membrane.<ref name="Morgan"/> | FFAs bind to hGPR40 by coordinating its free carboxyl group to three amino acids, <scene name='72/727085/Ffa_binding/1'>Arg183, Tyr2240, and Arg258</scene>, which are located close to the <scene name='72/727085/Hgpr40_transmane_active/1'>extracellular domain</scene> of hGPR40 on TM5, 6 and 7. Because of the close proximity of these residues to the extracellular domain and the dominantly hydrophobic nature of FFA’s, it is likely that ligand binding occurs close to the plane of the membrane.<ref name="Morgan"/> | ||