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

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.

 

Comments:

That's fascinating! Discovering a potential new neurotransmitter like creatine within synaptic vesicles is groundbreaking. The method of examining vesicle contents before fully understanding their function is an innovative approach.

From your description, it seems creatine exhibits characteristics akin to neurotransmitters, especially with its presence in synaptic vesicles and its role in calcium-dependent release after stimulation. Its impact on neocortical pyramidal neurons and the necessity of specific proteins like SLC6A8 for its uptake and release further emphasize its potential neurotransmitter function.

The connection between mutations in genes related to creatine synthesis or transport and intellectual disability in men adds significant clinical relevance to this discovery. Understanding how creatine operates as a neurotransmitter could potentially lead to insights into various neurological conditions and possibly pave the way for novel therapeutic interventions.

It's exciting to see this multi-dimensional exploration—biochemical, chemical, genetic, and electrophysiological—coming together to support the notion of creatine as a neurotransmitter, even if it hasn't reached the conclusive proof of established neurotransmitters yet.

The intricacies of the central nervous system and neurotransmission are complex, but this discovery certainly opens up new avenues for exploration and understanding. The potential implications for neuroscience and medicine are vast.

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