User:Dthackston3/sandbox

Vesicular Monoamine Transporter 1

I. Introduction A. A few sentences preceding the table of contents to introduce the topic 1. Introduce it as vesicular monoamine transporter 1 (VMAT1) and solute carrier family 18 member 1 (SLC18A1) 2. Mention the gene that is encoded by     3. Briefly describe its function (integral protein that moves monoamines into synaptic vesicles)

II. ToC A. Discovery B. Structure C. Localization D. Function E. Medical Implications

III. Discovery A. Discuss the cloning of the genes from rats and then humans 1. I only recently found this information and need time to go over it before knowing what will go in

IV. Structure A. Proteins 1. Glycoprotein, apparent weight 70 kDa 2. High degree of homology between VMAT1, VMAT2, and VAChT 3. Crystallographic structure not resolved a. 12 transmembrane domains -based on Kyte-Doolittle hydropathy analysis b. 10 transmembrane domains -based on MAXHOM alignment using "profile-fed neural network systems from Heidelburg" (PHD) program c. difference is that 10 TMD idea has TMD II and TMD IV in the vesicle lumen or cytoplasm 4. Variation a. VMAT1 is most distinct from other VATs in the N- and C- terminals and in the large glycosylated loop between TMD1 and TMD2 V. Localization A. Cell types which contain VMAT1 1. Endocrine cells/Neuroendocrine cells a. Chromaffin cells b. Enterochromaffin cells c. Small intensely fluorescent cells (SIF) 2. Absent from CNS nerve cells a. In contrast to VMAT2 3. Preference of cells for VMAT1 or VMAT2 varies among species B. Vesicle types which contain VMAT1 1. Large dense-core vesicles (LDCVs) a. Also contain catecholamines 2. Small synaptic vesicles (SSVs) a. Less prevalent b. Relation to vesicular acetylcholine transporter (VAChT) -Examined in PC12 cells (rat adrenal medulla cells) -Mixed phenotype for SSVs (have both) or two populations of SSVs (one for VMAT1 and one for VAChT) -Suggests higher adrenergic activity in LDCVs and higher cholinergic activity in SSVs

VI. Function A. Active transport of monoamines 1. Driving forces a. Transmembrane pH and H+ - ATPase -Inward transport of monoamine, outward transport of two protons -First proton changes transporter conformation to high monoamine affinity -Linkage thought to be to His419, in cytoplasmic domain between TMD X and XI            -Second proton changes conformation such that monoamine is pulled in and affinity is decreased -Linkage thought to be to Asp431, in TMD XI        b. Other links between transmembrane domains and functions -Pick a few (there are a lot) from the article to discuss here 2. Inhibition a. Reserpine (RES), TBZ, amphetamine less effective in inhibition of VMAT1 than VMAT2 b. Fenfluramine is more potent in VMAT1 B. Examples of specific areas that VMAT1 is used 1. Regulation of serotonin secretion in intestines 2. Modulation of gastrin processing 3. Protection of cells/tissues from cooling/rewarming injury 4. In pancreatic cancer

VII. Medical Implications A. Possible linkage to schizophrenia 1. SLC18A1 maps to chromosome 8p21.3, which is a locus with strong evidence of linkage to schizophrenia a. Polymorphic forms of VMAT1 gene may confer susceptibility 2. This was noted primarily in Japanese people B. Possible linkage to biopolar disorder/anxiety disorders 1. Studies show evidence of susceptibility in Europeans with polymorphic forms of VMAT1 gene 2. Locus is shared between schizophrenia and bipolar C. Further studies necessary VIII.References A. References will go here