Editing Succinic acid (section)

=== Extracellular signaling ===
Extracellular succinate can act as a signaling molecule with hormone-like functions in stimulating a variety of cells such as those in the blood, adipose tissues, immune tissues, liver, heart, retina and kidney.<ref name=Fonseca2016rev/> Extracellular succinate works by binding to and thereby activating the GPR91 (also termed [[SUCNR1]]<ref name="pmid35888775">{{cite journal | vauthors = Detraux D, Renard P | title = Succinate as a New Actor in Pluripotency and Early Development? | journal = Metabolites | volume = 12 | issue = 7 | date = July 2022 | page = 651 | pmid = 35888775 | pmc = 9325148 | doi = 10.3390/metabo12070651 | doi-access = free | url = }}</ref>) [[Receptor (biochemistry)|receptor]] on the cells that express this receptor. Most studies have reported that the GPR91 protein consists of 330 [[amino acid]]s although a few studies have detected a 334 amino acid product of ''GPR91'' gene.<ref name="pmid26808164">{{cite journal | vauthors = Gilissen J, Jouret F, Pirotte B, Hanson J | title = Insight into SUCNR1 (GPR91) structure and function | journal = Pharmacology & Therapeutics | volume = 159 | issue = | pages = 56–65 | date = March 2016 | pmid = 26808164 | doi = 10.1016/j.pharmthera.2016.01.008 | hdl = 2268/194560 | s2cid = 24982373 | url = https://orbi.uliege.be/bitstream/2268/194560/1/Gilissen%20et%20al%202016.pdf}}</ref> Arg<sup>99</sup>, His<sup>103</sup>, Arg<sup>252</sup>, and Arg<sup>281</sup> near the center of the GPR91 protein generate a positively charged binding site for succinate. GPR91 resides on its target cells' [[Cell membrane|surface membrane]]s with its binding site facing the extracellular space.<ref name=Gilissen2016rev/> It is a [[G protein-coupled receptor]] sub-type of receptor<ref name=Gilissen2016rev>{{Cite journal|last1=Gilissen|first1=Julie|last2=Jouret|first2=François|last3=Pirotte|first3=Bernard|last4=Hanson|first4=Julien|date=2016-03-01|title=Insight into SUCNR1 (GPR91) structure and function|journal=Pharmacology & Therapeutics|volume=159|pages=56–65|doi=10.1016/j.pharmthera.2016.01.008|pmid=26808164|hdl=2268/194560|s2cid=24982373 |url=http://orbi.ulg.ac.be/handle/2268/194560|hdl-access=free}}</ref> that, depending on the cell type bearing it, interacts with multiple [[G proteins]] subtypes including [[Gs alpha subunit|G<sub>s</sub>]], [[Gi alpha subunit|G<sub>i</sub>]] and [[Gq alpha subunit|G<sub>q</sub>]]. This enables GPR91 to regulate a multitude of signaling outcomes.<ref name=Fonseca2016rev/>

Succinate has a high affinity for GPR91, with an [[EC50|EC<sub>50</sub>]] (i.e., concentration that induces a half maximal response) for stimulating GPR91 in the 20–50 μM range. Succinate's activation of the GPR91 receptor simulates a wide range of cell types and [[physiological]] responses (see [[SUCNR1#Functions regulated by SUCNR1|Functions regulated by SUCNR1]]).<ref name="pmid34301438">{{cite journal | vauthors = Fernández-Veledo S, Ceperuelo-Mallafré V, Vendrell J | title = Rethinking succinate: an unexpected hormone-like metabolite in energy homeostasis | journal = Trends in Endocrinology and Metabolism | volume = 32 | issue = 9 | pages = 680–692 | date = September 2021 | pmid = 34301438 | doi = 10.1016/j.tem.2021.06.003 | s2cid = 236097682 | url = }}</ref><ref name="pmid33279412">{{cite journal | vauthors = Krzak G, Willis CM, Smith JA, Pluchino S, Peruzzotti-Jametti L | title = Succinate Receptor 1: An Emerging Regulator of Myeloid Cell Function in Inflammation | journal = Trends in Immunology | volume = 42 | issue = 1 | pages = 45–58 | date = January 2021 | pmid = 33279412 | doi = 10.1016/j.it.2020.11.004 | s2cid = 227522279 | url = }}</ref>

==== Effect on adipocytes ====
In [[adipocyte]]s, the succinate-activated GPR91 signaling cascade inhibits [[lipolysis]].<ref name=Fonseca2016rev/>

==== Effect on the liver and retina ====
Succinate signaling often occurs in response to hypoxic conditions. In the liver, succinate serves as a [[Paracrine signalling|paracrine]] signal, released by anoxic [[hepatocyte]]s, and targets [[stellate cell]]s via GPR91.<ref name=Fonseca2016rev /> This leads to stellate cell activation and fibrogenesis. Thus, succinate is thought to play a role in liver [[homeostasis]]. In the retina, succinate accumulates in [[retinal ganglion cell]]s in response to ischemic conditions. [[Autocrine signalling|Autocrine]] succinate signaling promotes retinal [[neovascularization]], triggering the activation of angiogenic factors such as [[Vascular endothelial growth factor|endothelial growth factor]] (VEGF).<ref name=Fonseca2016rev/><ref name=Gilissen2016rev/>

==== Effect on the heart ====
Extracellular succinate regulates [[Cardiac muscle cell|cardiomyocyte]] viability through GPR91 activation; long-term succinate exposure leads to pathological cardiomyocyte [[hypertrophy]].<ref name=Fonseca2016rev/> Stimulation of GPR91 triggers at least two signaling pathways in the heart: a [[MAP2K1|MEK1/2]] and [[MAPK3|ERK1/2]] pathway that activates hypertrophic gene expression and a [[phospholipase C]] pathway which changes the pattern of Ca<sup>2+</sup> uptake and distribution and triggers [[Calmodulin|CaM]]-dependent hypertrophic gene activation.<ref name="Fonseca2016rev" />

==== Effect on immune cells ====
SUCNR1 is highly expressed on immature [[dendritic cell]]s, where succinate binding stimulates [[chemotaxis]].<ref name=Gilissen2016rev/> Furthermore, SUCNR1 synergizes with [[toll-like receptor]]s to increase the production of [[proinflammatory cytokine]]s such as [[Tumor necrosis factor alpha|TNF alpha]] and [[Interleukin 1 beta|interleukin-1beta]].<ref name=Mills2014rev/><ref name=Gilissen2016rev/> Succinate may enhance [[Adaptive immune system|adaptive immunity]] by triggering the activity of antigen-presenting cells that, in turn, activate [[T cell|T-cells]].<ref name=Mills2014rev/>

==== Effect on platelets ====
SUCNR1 is one of the highest expressed G protein-coupled receptors on human platelets, present at levels similar to [[P2Y12|P2Y<sub>12</sub>]], though the role of succinate signaling in [[Platelet|platelet aggregation]] is debated. Multiple studies have demonstrated succinate-induced aggregation, but the effect has high inter-individual variability.<ref name=Ariza2012rev/>

==== Effect on the kidneys ====
Succinate serves as a modulator of blood pressure by stimulating renin release in [[macula densa]] and [[Juxtaglomerular cell|juxtaglomerular apparatus cells]] via GPR91.<ref>{{Cite journal|last1=Peti-Peterdi|first1=János|last2=Gevorgyan|first2=Haykanush|last3=Lam|first3=Lisa|last4=Riquier-Brison|first4=Anne|date=2012-06-23|title=Metabolic control of renin secretion|journal=Pflügers Archiv: European Journal of Physiology|volume=465|issue=1|pages=53–58|doi=10.1007/s00424-012-1130-y|issn=0031-6768|pmc=4574624|pmid=22729752}}</ref> Therapies targeting succinate to reduce cardiovascular risk and hypertension are currently under investigation.<ref name=Ariza2012rev/>