Astrocytes and neurons communicate via a monocarboxylic acid shuttle

Dirk Roosterman,Graeme S Cottrell

doi:10.3934/neuroscience.2020007

Abstract

Since formulation of the Astrocyte-Neuron Lactate Shuttle (ANLS) hypothesis in 1994, the hypothesis has provoked criticism and debate. Our review does not criticise, but rather integrates experimental data characterizing proton-linked monocarboxylate transporters (MCTs) into the ANLS. MCTs have wide substrate specificity and are discussed to be in protein complex with a proton donor (PD). We particularly focus on the proton-driven transfer of l-lactic acid (l-lacH) and pyruvic acid (pyrH), were PDs link MCTs to a flow of energy. The precise nature of the PD predicts the activity and catalytic direction of MCTs. By doing so, we postulate that the MCT4·phosphoglycerate kinase complex exports and at the same time in the same astrocyte, MCT1·carbonic anhydrase II complex imports monocarboxylic acids. Similarly, neuronal MCT2 preferentially imports pyrH. The repertoire of MCTs in astrocytes and neurons allows them to communicate via monocarboxylic acids. A change in imported pyrH/l-lacH ratio in favour of l-lacH encodes signals stabilizing the transit of glucose from astrocytes to neurons. The presented astrocyte neuron communication hypothesis has the potential to unite the community by suggesting that the exchange of monocarboxylic acids paves the path of glucose provision.

Highlights

Astrocyte Neuron Communication (ANC) predicts that MCT2ꞏCAIV is formed to import monocarboxylic acids, but ANC does not exclude functional connection of MCT2 to other proton donor (PD), which can change the catalytic direction of MCT2 from import to export
During the development of our theory of ANC and its role in memory formation and consolidation, we may have omitted mentioning many brilliant and highly informative manuscripts in this area. Our impact in this scientific field is turning the catalytic direction of MCT1 from export to import, which changes the Astrocyte-Neuron Lactate Shuttle (ANLS) hypothesis from “food for hungry neurons” to astrocyte neuron communication, ANC
In contrast to ANLS, which is a concept based on free diffusion and merges export and import of L-lacH at reversibly acting monocarboxylate transporters (MCTs) producing a deadlock situation, ANC allows activated neurons to consume more glucose and more L-lacH, at the same time in the same cell

Summary

Introduction

“The important point here is not so much to decide, based on the actual pieces of evidence, whether an hypothesis is right or wrong but rather to point out what is heuristically valid in it, what have we learned, what remains to be assessed, what new hypothesis can be proposed and which experiments are critical for it” [1]. Our concept of Astrocyte Neuron Communication (ANC) is guided by the tentative 4th law of thermodynamics This law of nature predicts that a flow of energy is sufficient to form ordered structures [4,5,6]. Enzyme complexes are examples of highly ordered structures Acids, such as carbonic acid (H2CO3), carry an active proton (H+). Whereas ANLS and NALS are based on concepts whereby enzymes catalyse a process leading to maximal entropy and transporters to a concentration equilibrium, ANC uses proton-linked MCTs directly coupled to glucose metabolism. ANC is biophysical concept, where glucose metabolism is the reverberatory activity inducing cell assembly and a flow of energy inducing ordered structures [4,10,11]. Before considering ANC, we must first explore the properties of MCTs present on astrocytes and neurons

Astrocytic and neuronal MCTs

Encoding the signal

Astrocytes transit glucose

Discussion and conclusion