β-N-methylamino-l-alanine is a non-competitive inhibitor of vesicular monoamine transporter 2

Chanté Kennedy; Rianita van Onselen; Tim G Downing

doi:10.1016/j.toxicon.2022.106978

β-N-methylamino-l-alanine is a non-competitive inhibitor of vesicular monoamine transporter 2

Toxicon. 2023 Jan 15:222:106978. doi: 10.1016/j.toxicon.2022.106978. Epub 2022 Nov 19.

Authors

Chanté Kennedy¹, Rianita van Onselen², Tim G Downing³

Affiliations

¹ Department of Biochemistry and Microbiology, Nelson Mandela University, P.O. Box 77000, Port Elizabeth, 6021, South Africa. Electronic address: Chanteleigh-ann.Kennedy@mandela.ac.za.
² Department of Biochemistry and Microbiology, Nelson Mandela University, P.O. Box 77000, Port Elizabeth, 6021, South Africa; Biomedical Research and Innovation Platform, South African Medical Research Council, Cape Town, South Africa. Electronic address: Rianita.VanOnselen@mrc.ac.za.
³ Department of Biochemistry and Microbiology, Nelson Mandela University, P.O. Box 77000, Port Elizabeth, 6021, South Africa. Electronic address: Tim.Downing@mandela.ac.za.

PMID: 36410456
DOI: 10.1016/j.toxicon.2022.106978

Abstract

The neurotoxic, non-proteinogenic amino acid β-N-methylamino-l-alanine (BMAA) has been implicated in the development of neurodegenerative diseases; however, the mechanism(s) and mode(s) of toxicity remain unclear. Similarities in the neuropathology and behavioural deficits of neonatal rats exposed to either BMAA or reserpine, a known vesicular monoamine transporter 2 (VMAT2) inhibitor, suggest a similar mode of action. The aims of this study were therefore to determine if BMAA could prevent the uptake of serotonin into dense granules via inhibition of VMAT2, and, if so, the type of inhibition caused by BMAA. Exposing platelet dense granules to BMAA resulted in a concentration-dependent reduction in serotonin uptake. The inhibition of VMAT2 was non-competitive. The findings from this study support previous reports that BMAA-associated neuropathologies in a neonatal rat model may be due to VMAT2 inhibition during critical periods of neurogenesis.

Keywords: ALS/PDC; Transporter kinetics; Vesicular monoamine transporter 2; dense Granules; β-N-Methylamino-l-alanine.

MeSH terms

Amino Acids / metabolism
Amino Acids, Diamino* / metabolism
Amino Acids, Diamino* / toxicity
Animals
Neurotoxins / pharmacology
Rats
Serotonin
Vesicular Monoamine Transport Proteins*

Substances

beta-N-methylamino-L-alanine
Vesicular Monoamine Transport Proteins
Serotonin
Amino Acids, Diamino
Amino Acids
Neurotoxins