Despite a movement away from dopamine-focused Parkinson’s disease (PD) research a recent surge of evidence now suggests that altered vesicular storage of dopamine may contribute to the demise of the nigral neurons in this disease. from remaining midbrain dopamine neurons and protect against neurotoxic insults. Thus the development of drugs to enhance the storage of release of dopamine may be a fruitful avenue of research for PD. vesicular function is beneficial to the dopamine system. Mice with elevated VMAT2 levels (VMAT2-HI) have an increased capacity for the storage of dopamine in their neurons which results in increased total dopamine levels increased dopamine release and protection from neurotoxic insult by MPTP . This means that a small molecule capable of enhancing VMAT2 function may increase neuronal dopamine output while also protecting those cells from intracellular stressors. These findings from the VMAT2-HI mice provide a crucial stepping stone to understanding the uppermost limits of the dopamine vesicle suggesting that VMAT2 modulation may be a viable therapeutic approach to address deficits in neurotransmitters like dopamine. VMAT2 function in human disease Multiple groups have reported the importance of vesicular function in human parkinsonism. Over 50 years after the key finding from the Ehringer and Hornykievicz  Pifl reported that post-mortem PD brains show dramatically reduced F3 VMAT2-mediated vesicular filling greater than what could be explained by terminal loss alone . This demonstrates that impaired packaging of dopamine into vesicles may be a key player in the disease process. These results also complement recent findings including higher cytosolic dopamine turnover in PD patients  and a familial VMAT2 mutation that dramatically reduces vesicular filling and causes an infantile parkinsonian condition with profound motor and cognitive Roscovitine (Seliciclib) impairments . Additionally there is mounting evidence that increased VMAT2 level or function protects against PD. Glatt et al. exhibited that a gain in VMAT2 function protects against the development of PD . Brighina et al. associated two SNPs in the promoter region of the VMAT2 gene with a reduced PD risk suggesting that increases to VMAT2 level confer protection to the disease . Thus vesicular function may oppose the vulnerability of midbrain dopamine neurons to other factors that influence PD outcome whether genetic (PD-associated mutations) or environmental (toxic insult). Therapeutic potential of vesicular modulation It is time to revisit the idea of optimizing the function of existing dopamine neurons in the PD brain . By manipulating vesicular filling through increased VMAT2 level or function the benefits in a PD patient would be threefold: improved efficacy of newly synthesized dopamine via L-DOPA treatment increased dopamine neurotransmission from remaining dopamine Roscovitine (Seliciclib) neurons and protection from either exogenous or endogenous neurotoxic insults. With the latest work from our lab and others it appears to be more plausible than ever before to take advantage of the malleable Roscovitine (Seliciclib) nature of the synaptic dopamine vesicle. Interestingly the VMAT2-HI Roscovitine (Seliciclib) mice mentioned above also show improved outcomes on steps of depressive and anxiety-like actions both of which are likely mediated by monoamines beyond just dopamine . Thus it is possible that a VMAT2-targeted therapeutic strategy may have beneficial effects in other monoamine-deficient diseases like depression for example. Alternatively ligands that are also selective for plasma membrane transporters (DAT on dopamine neurons SERT on serotonin neurons or NET on norepinephrine neurons) would allow for more transmitter system-specific VMAT2 modulation. Finally one must not forget that other mediators of vesicular dopamine storage may provide alternate targets for the development of therapeutics. In this way our understanding of the benefits of increased VMAT2 function could serve as a proxy for another vesicular protein target. VMAT2 in the winner’s circle In conclusion the delicate balance of dopamine in the neuronal terminal is usually a complicated game of keeping the neurotransmitter in the right place at the right time. Too much dopamine left unpackaged and the cytosolic environment becomes precarious. With too little dopamine in the system the neurons drop signaling efficacy which manifests itself as a parkinsonism-like behavior. Luckily there appears to be a ‘dopamine nice spot’ where one can take advantage of an additional vesicular capacity thereby Roscovitine (Seliciclib) improving L-DOPA efficacy increasing transmitter output and protecting cells from toxic insult. Based on the.