Suggestion of creatine as a new neurotransmitter by approaches ranging from chemical analysis and biochemistry to electrophysiology

Author:

Bian Xiling12,Zhu Jiemin12,Jia Xiaobo12ORCID,Liang Wenjun34,Yu Sihan14,Li Zhiqiang1,Zhang Wenxia135,Rao Yi12345ORCID

Affiliation:

1. Laboratory of Neurochemical Biology, PKU-IDG/McGovern Institute for Brain Research, Peking-Tsinghua Center for Life Sciences, School of Life Sciences, Department of Chemical Biology, College of Chemistry and Chemical Engineering, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University

2. Chinese Institute for Brain Research (CIBR)

3. Chinese Institutes of Medical Research, Capital Medical University

4. Changping Laboratory, Yard 28, Science Park Road, Changping District

5. Institute of Molecular Physiology, Shenzhen Bay Laboratory

Abstract

The discovery of a new neurotransmitter, especially one in the central nervous system, is both important and difficult. We have been searching for new neurotransmitters for 12 y. We detected creatine (Cr) in synaptic vesicles (SVs) at a level lower than glutamate and gamma-aminobutyric acid but higher than acetylcholine and 5-hydroxytryptamine. SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in Slc6a8 and Agat mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP-dependent manner. Our biochemical, chemical, genetic, and electrophysiological results are consistent with the possibility of Cr as a neurotransmitter, though not yet reaching the level of proof for the now classic transmitters. Our novel approach to discover neurotransmitters is to begin with analysis of contents in SVs before defining their function and physiology.

Funder

Chinese Academy of Medical Sciences

Chinese Institute for Brain Research

Peking-Tsinghua Center for Life Sciences

Changping Laboratory

National Natural Science Foundation of China

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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