on a loop between TMD I and TMD II. In biology, the vesicle matrix refers to the material or tissue between cells in which more specialized structures are embedded. Two of the glycosylation sites, the N-linked glycosylation terminal and C-linked terminal, are located in the cytosolic portion of the vesicle.Erickson, Eiden, & Hoffman, 1992 The highest amount of genetic variance between VMAT1 and VMAT2 exists near the N- and C- terminals in the cytosolic phase, and in the glycosylated loop between TMDs I and II. C-terminus and VMAT trafficking cycle Several motifs involved in the VMAT trafficking cycle are believed to be encoded in the C-terminus. A dileucine motif in the C-terminus is required for VMAT2 endocytosis. Studies suggest the acidic residues in the dileucine motif sort VMAT2 away from constitutive secretory vesicles and into the regulated secretory pathway. The hydrophobic residues in the dileucine motif are thought to couple with the acidic residues as a single unit to help sort VMAT2 to large dense course vesicles. Acidic glutamate residues located upstream of the dileucine motif are known to be important for localization of VMAT2 to large dense core vesicles; these residues are also conserved in VMAT1. Genetic expression and transporter regulation Although both VMAT1 and VMAT2 are encoded by two different genes, the individual genetic sequences demonstrate high homology. Polymorphisms in VMAT2 that affect regulation and quantitative expression may pose genetic risk factors for PD. A specific VMAT1 gene (SLC18A1) has several associated polymorphisms, which have a locus 8p21.3 that has been strongly connected to schizophrenia susceptibility. Over-expression of VMAT2 results in increased secretion of neurotransmitter upon cell stimulation. Data suggests that deletion of the VMAT2 genes does not affect the size of small clear-core vesicles. VMATs may be regulated by changes in transcription, post-transcriptional modifications such as phosphorylation and mRNA splicing of exons, and vesicular transport inactivation facilitated by heterotrimeric G-proteins, which are thought to be possessed by chromaffin granules, and have shown to regulate small clear-core vesicles. Specific heterotrimeric G-protein type regulation is tissue-dependent for VMAT2; it is not known whether this is the case for VMAT1. Heterotrimeric G-protein Gαo2 decreases VMAT1 activity in pancreatic and adrenal medulla cells, and activates heterotrimeric G-proteins to inhibit VMAT2 activity in the brain, regardless of whether they are localized on small clear-core or large-dense-core vesicles. The activated heterotrimeric G-protein Gαq downregulates VMAT2-mediated serotonin transport in blood platelets, but not in