VARIANTS OF THE PRIMATE VESICULAR MONOAMINE TRANSPORTER-2

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The vesicular monoamine transporter (VMAT2) transports, stores and releases neurotransmitters in brain and the amphetamine class of abused drugs. It is implicated in neuroprotection, as it sequesters the neurotoxin MPP+. Human striatum generates three VMAT2 immunoreactive proteins, 75 kDa, 52-55 kDa, and 45 kDa, of which the 55 kDa band is considered the native protein and a prmary focus of research. We questioned whether the 55 kDa band is the native VMAT2 protein. Results: Human or monkey brain VMAT2 and cloned hVMAT2 yielded three immunoreactive bands, 65-75 kDa, 52-55 kDa and 45 kDa. Inhibition of glycosylation or deglycosylation uniformly resulted in a predominant 45 kDa immunoreactive band. A VMAT2 protein, generated from a mutant form of the VMAT2 gene was functional, albeit at reduced levels. Discussion: The 75 kDa and 55 kDa protein species appear to be glycosylated forms of a native VMAT2 protein that migrates at 45 kDa. The 45kDa band may represent a native functional form of the VMAT2, or the 55kDa native protein migrates more rapidly than MW markers. Alternatively, the 45kDa band may reflect non-ATG (non-AUG) translation initiation, other than the predicted ATG in exon 2, with precedent for non-AUG translation initiation sites. The ratio of VMAT2 immunoreactive proteins varies in human brain, and may be relevant to physiological or pathological processes and drug response.