What is it about?

By using brain neurons, we identified a novel molecular mechanism for neurotransmitter release regulated by two autism candidate proteins, SCAMP5 (secretory carrier membrane protein 5) and NHE6 (Na+/H+ exchanger 6). Presynaptic localization of NHE6 is mediated by direct interaction with SCAMP5. When their interaction is inhibited, proper localization of NHE6 is disrupted and the lumen of synaptic vesicle becomes hyperacidification. This leads to the reduced amount of glutamate (neurotransmitter at excitatory neuron) release from presynaptic neurons, resulting in severe defects in synaptic transmission and physiological functions of neuronal activity.

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Why is it important?

Researches about neurodevelopmental disorders at cellular level mainly dealt with the morphological changes of synaptic structures and postsynaptic functions. Recent studies suggested that several protein mutations related with the neurotransmitter release cause the neurodevelopmental disorders, however, how the protein mutations induce dysfunction in neurotransmitter release was not clearly identified. In this study, we found that autism-related proteins, SCAMP5 and NHE6, play an important role in adjusting the neurotransmitter release at presynaptic neurons. In addition, our research data provide evidences for understanding the pathological mechanism of multiple neuronal diseases because both SCAMP5 and NHE6 are considerably engaged in various neurodevelopmental, neuropsychiatric and neurodegenerative diseases.


Before this study, we did not know that which kind of cation/hydrogen exchangers exist at synaptic vesicle and regulate the uptake of neurotransmitters into synaptic vesicles. We could just speculate that the most promising candidates were the endosomal subtypes of cation/hydrogen exchanger, NHE6 and NHE9. NHE9 knockout study by other research group revealed that NHE9 regulated the endosomal pH rather than that of synaptic vesicles, so we could focus on NHE6 as a modulator of synaptic vesicle pH and neurotransmitter uptake into synaptic vesicles. We discovered that NHE6 is the molecule which resides on synaptic vesicle and regulate glutamate quantal size at excitatory synapses. We hope that our results give help to scientists for understanding molecular mechanism of neurodevelopmental disorders and finding therapeutic target for autism.

Unghwi Lee
Seoul National University

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This page is a summary of: SCAMP5 plays a critical role in axonal trafficking and synaptic localization of NHE6 to adjust quantal size at glutamatergic synapses, Proceedings of the National Academy of Sciences, December 2020, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2011371118.
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