Dopamine transport proteins VMAT2 and DAT. (public domain illustration by John Schmidt)
I’m trying to establish a more formal system for a “journal club”, but for now we can use this blog. [Update, Spring 2012, see this journal club page.]
This blog post starts the “journal club”. “Journal club” means that participants will each pick a topic and find a related journal article.
Here I introduce the article called, “Physical and Functional Interaction between the Dopamine Transporter and the Synaptic Vesicle protein Synaptogyrin-3“.
This journal article is medically important because many pharmacological agents alter dopamine (DA) transport and brain function. Methamphetamine is a major drug of abuse and it disrupts normal dopamine transport, but the exact mechanism is still mysterious. As shown in the diagram, two major dopamine transport proteins are DAT and VMAT2. DAT normally allows for re-uptake of dopamine from the synaptic cleft. VMAT2 is important for transport of dopamine from the cytoplasm into synaptic vesicles.
Egaña et al. report some experiments suggesting that there might be a complex of physically interacting proteins including DAT, synaptogyrin-3, and VMAT2. Synaptogyrin-3 is a synaptic vesicle protein. It was also recently suggested that VMAT2 forms a protein complex with tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC, also called DOPA-decarboxylase).
Why is this medically important? Amphetamines cause depletion of dopamine from synaptic vesicles. If DAT and VMAT2 are physically linked then it might be that amphetamine binding to cell surface transporters like DAT can alter the function of VMAT2. VMAT2 seems to be the binding site for chemicals such as lobelane that can inhibit methamphetamine-evoked DA release from neurons. There might be a previously unrecognized macromolecular complex of proteins linking cell surface transport proteins such as DAT to VMAT2. If such a complex of linked dopamine transport proteins does exist, study of how DAT and VMAT2 interact might help us better understand medical conditions such as Parkinson disease, dystonia, depression, schizophrenia, attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, and drug addiction.
Note: The current conventional thinking about how methamphetamine alters dopamine storage and transport does not involve any physical link between the cell surface DAT and synaptic vesicles.
Related reading. A Receptor Mechanism for Methamphetamine Action in Dopamine Transporter Regulation in Brain
Is Parkinson’s disease a vesicular dopamine storage disorder? J. Neurosci. 2014 June
Comments are welcome here about the article “Physical and Functional Interaction between the Dopamine Transporter and the Synaptic Vesicle protein Synaptogyrin-3” and dopamine transport in the brain.
If you want to participate in the “journal club”, find a recently published journal article and prepare a brief written account of why the article is of interest to you. Contact me and I can make it possible for you to post and share your contribution to the “journal club” here in blog format.