Putative Receptors Underpinning L-Lactate Signalling in Locus Coeruleus

Valentina Mosienko, Ali Rasooli-Nejad, Kasumi Kishi, Matt De Both, David Jane, Matthew Huentelman, Sergey Kasparov, Anja Teschemacher

Research output: Contribution to journalArticle (Academic Journal)

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Abstract

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.
Original languageEnglish
Pages (from-to)365-380
Number of pages16
JournalNeuroglia
Volume1
Issue number2
DOIs
Publication statusPublished - 16 Nov 2018

Keywords

  • L-lactate
  • hydroxy-carboxylic acid receptor
  • OR51E2
  • GPR4
  • GPR137
  • cAMP
  • locus coeruleus
  • noradrenaline
  • next generation sequencing
  • structure–activity relationship

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