Putative Receptors Underpinning l-Lactate Signalling in Locus Coeruleus

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

doi:10.3390/neuroglia1020025

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.

Highlights

Astrocytes, the electrically nonexcitable “cousins” of neurones, are strategically placed at the interface between the periphery and neuronal networks of the central nervous system
Since glycolysis is very fast compared to the mitochondrial oxidation of pyruvate, the contribution of glycolysis to the pool of ATP may be comparable to that originating from oxidative phosphorylation [2], especially during peaks of high metabolic demand
Since we previously showed that Gs-coupling was involved in LL-mediated stimulation of noradrenergic transmission [20], we checked our transcriptomic data and found OR51E2 expression in locus coeruleus (LC) tissue, but were unable to confirm its expression in isolated LC neurones (Table 2)

Summary

Introduction

Astrocytes, the electrically nonexcitable “cousins” of neurones, are strategically placed at the interface between the periphery and neuronal networks of the central nervous system. Among other functions, they handle the import and distribution of glucose, the main energy substrate used by the brain, as well as its storage in the form of glycogen [1]. If glycolysis is followed by oxidative phosphorylation, nearly 20 times as much ATP can be produced. Since glycolysis is very fast compared to the mitochondrial oxidation of pyruvate, the contribution of glycolysis to the pool of ATP may be comparable to that originating from oxidative phosphorylation [2], especially during peaks of high metabolic demand. The energetic or functional advantages of this metabolic imbalance are still controversial

Methods

Results

Conclusion