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Open AccessArticle

Putative Receptors Underpinning l-Lactate Signalling in Locus Coeruleus

1
Pharmacology and Neuroscience, School of Physiology, University of Bristol, Bristol BS8 1TD, UK
2
Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter EX4 4PS, UK
3
Neuroscience Research Centre, Medical University Berlin—Charité, D-10115 Berlin, Germany
4
Institute of Science and Technology IST Austria, 3400 Klosterneuburg, Austria
5
Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ 85004, USA
*
Author to whom correspondence should be addressed.
Received: 14 October 2018 / Revised: 5 November 2018 / Accepted: 7 November 2018 / Published: 16 November 2018
The importance of astrocytic l-lactate (LL) for normal functioning of neural circuits such as those regulating learning/memory, sleep/wake state, autonomic homeostasis, or emotional behaviour is being increasingly recognised. l-Lactate can act on neurones as a metabolic or redox substrate, but transmembrane receptor targets are also emerging. A comparative review of the hydroxy-carboxylic acid receptor (HCA1, formerly known as GPR81), Olfactory Receptor Family 51 Subfamily E Member 2 (OR51E2), and orphan receptor GPR4 highlights differences in their LL sensitivity, pharmacology, intracellular coupling, and localisation in the brain. In addition, a putative Gs-coupled receptor on noradrenergic neurones, LLRx, which we previously postulated, remains to be identified. Next-generation sequencing revealed several orphan receptors expressed in locus coeruleus neurones. Screening of a selection of these suggests additional LL-sensitive receptors: GPR180 which inhibits and GPR137 which activates intracellular cyclic AMP signalling in response to LL in a heterologous expression system. To further characterise binding of LL at LLRx, we carried out a structure–activity relationship study which demonstrates that carboxyl and 2-hydroxyl moieties of LL are essential for triggering d-lactate-sensitive noradrenaline release in locus coeruleus, and that the size of the LL binding pocket is limited towards the methyl group position. The evidence accumulating to date suggests that LL acts via multiple receptor targets to modulate distinct brain functions. View Full-Text
Keywords: l-lactate; hydroxy-carboxylic acid receptor; OR51E2; GPR4; GPR137; cAMP; locus coeruleus; noradrenaline; next generation sequencing; structure–activity relationship l-lactate; hydroxy-carboxylic acid receptor; OR51E2; GPR4; GPR137; cAMP; locus coeruleus; noradrenaline; next generation sequencing; structure–activity relationship
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MDPI and ACS Style

Mosienko, V.; Rasooli-Nejad, S.; Kishi, K.; De Both, M.; Jane, D.; Huentelman, M.J.; Kasparov, S.; Teschemacher, A.G. Putative Receptors Underpinning l-Lactate Signalling in Locus Coeruleus. Neuroglia 2018, 1, 365-380. https://0-doi-org.brum.beds.ac.uk/10.3390/neuroglia1020025

AMA Style

Mosienko V, Rasooli-Nejad S, Kishi K, De Both M, Jane D, Huentelman MJ, Kasparov S, Teschemacher AG. Putative Receptors Underpinning l-Lactate Signalling in Locus Coeruleus. Neuroglia. 2018; 1(2):365-380. https://0-doi-org.brum.beds.ac.uk/10.3390/neuroglia1020025

Chicago/Turabian Style

Mosienko, Valentina; Rasooli-Nejad, Seyed; Kishi, Kasumi; De Both, Matt; Jane, David; Huentelman, Matt J.; Kasparov, Sergey; Teschemacher, Anja G. 2018. "Putative Receptors Underpinning l-Lactate Signalling in Locus Coeruleus" Neuroglia 1, no. 2: 365-380. https://0-doi-org.brum.beds.ac.uk/10.3390/neuroglia1020025

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