Active transport of<unk> s Driving force An example of secondary active transport The active transport of<unk> s from the cytosol into storage vesicles operates against a large (>105) concentration gradient. Secondary active transport is the type of active transport used, meaning that<unk>  is an antiporter. This transport is facilitated via proton gradient generated by the protein proton ATPase. The inward transport of the<unk>  is coupled with the efflux of two protons per<unk> . The first proton is thought to cause a change in<unk> 's conformation, which pushes a high affinity amine binding site, to which the<unk>  attaches. The second proton then causes a second change in the conformation which pulls the<unk>  into the vesicle and greatly reduces the affinity of the binding site for amines. A series of tests suggest that His419, located between TMDs X and XI, plays the key role in the first of these conformational changes, and that Asp431, located on TMD XI, does likewise during the second change. Inhibition Several reuptake inhibitors of<unk>  are known to exist, including reserpine (RES), tetrabenazine (TBZ), dihydrotetrabenazine (DTBZOH), and ketanserin (KET). It is thought that RES exhibits competitive inhibition, binding to the same site as the<unk>  substrate, as studies have shown that it can be displaced via introduction of norepinephrine. TBZ, DTBZOH, and KET are thought to exhibit non-competitive inhibition, instead binding to allosteric sites and decreasing the activity of the<unk> rather than simply blocking its substrate binding site. It has been found that these inhibitors are less effective at inhibiting<unk>  than<unk> , and the inhibitory effects of the tetrabenazines on<unk>  is negligible. Clinical significance Pancreatic cancer The expression of<unk>  in healthy endocrine cells was compared to<unk>  expression in infants with hyperinsulinemic hypoglycemia and adults with pancreatic endocrine tumors. Through immunohistochemistry (IHC) and in situ hybridization (ISH), they found<unk>  and<unk>  were located in mutually exclusive cell types, and that in insulinomas<unk>  activity disappeared, suggesting that if only<unk>  activity is present in the endocrine system, this type of cancer is likely. Digestive system<unk>  also has effects on the modulation of gastrin processing in G cells. These intestinal endocrine cells process amine precursors, and<unk>  pulls them into vesicles for storage. The activity of<unk>  in these cells has a seemingly inhibitory effect on the processing of gastrin. Essentially, this means that certain compounds in the gut can be taken into these G cells and either amplify or inhibit the function of<unk> , which will impact gastrin processing (conversion from G34 to G17). Additionally,<unk>  is known to play a role in the uptake and secretion of serotonin in the gut. Enterochromaffin cells in the intestines will secrete serotonin in response to the activation of certain mechanosensors. The regulation of serotonin in the gut is critically important, as it modulates appetite and controls intestinal contraction. Protection against hypothermia Presence of<unk>  in cells has been shown to protect them from the damaging effects of cooling and rewarming associated with hypothermia. Experiments were carried out on aortic and kidney cells and tissues. Evidence was found that an accumulation of serotonin using<unk>  and TPH1 allowed for the subsequent release of serotonin when exposed to cold temperatures. This allows cystathionine beta synthase (CBS) mediated generation of H2S. The protection against the damage caused by hypothermia is due to a reduction in the generation of reactive oxygen species (ROS), which can induce apoptosis, due to the presence of H2S. Mental disorders<unk>  (SLC18A1) maps to a shared bipolar disorder(BPD)/schizophrenia locus, which is located on chromosome 8p21. It is thought that disruption in transport of<unk>  neurotransmitters due to variation in the<unk>  gene may be relevant to the etiology of these mental disorders. One study looked at a population of European descent, examining the genotypes of a bipolar group and a control group. The study confirmed expression of<unk>  in the brain at a protein and mRNA level, and found a significant difference between the two groups, suggesting that, at least for people of European descent, variation in the<unk>  gene may confer susceptibility. A second study examined a population of Japanese individuals, one group healthy and the other schizophrenic. This study resulted in mostly inconclusive findings, but some indications that variation in the<unk>  gene would confer susceptibility to schizophrenia in Japanese women. While these studies provide some promising insight into the cause of some of the most prevalent mental disorders, it is clear that additional research will be necessary in order to gain a full understanding.
Vesicular monoamine transporter 1
Glutamate transporter
Neurotransmitter transporter
Norepinephrine transporter
Thiamine transporter 1
Sodium-chloride symporter
Zinc transporter 8
Prolactin-releasing peptide receptor