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PharmGKB Submission Update

PharmGKB Submission Update: VI. PMT Submissions of Genetic Variations in Neurotransmitter Transporters (SLC6, SLC17, and SLC18) to the PharmGKB Network

Departments of Biopharmaceutical Sciences (I.B., M.S., R.A.C., C.B., E.G.B., D.L.K., K.M.G.), Pharmaceutical Chemistry (C.C.H., D.S., M.K., S.J.J., T.E.F.), and Biochemistry and Biophysics (I.H.), University of California, San Francisco, San Francisco, California; Department of Neurology and Physiology, School of Medicine, University of California, San Francisco, San Francisco, California (R.H.E.); Genomics Core Facility, Program in Human Genetics (I.H.), University of California, San Francisco, San Francisco, California (E.J.C., T.R.T., W.C., M.D.L.C.); and Lung Biology Center, San Francisco General Hospital, San Francisco, California (E.G.B.)

Category: genotype

Project: Pharmacogenetics of Membrane Transporters

Table 1 provides HUGO Gene Nomenclature Committee (HGNC) symbols, PharmGKB submission URLs, submission dates, and release dates. Table 2 provides HGNC symbols, HGNC names, synonyms, GenBank accession numbers, and locus IDs.

Pharmacogenetic Significance: Genetic variation in the SLC6, SLC17, and SLC18 families of neurotransmitter transporters may result in altered expression and/or function of proteins (Tables 1 and 2). Since neurotransmitter transporters are involved in the regulation of signaling among neurons in the central and peripheral nervous system, genetic variation in these transport proteins has important pathophysiological and pharmacotherapeutic implications. In addition, many of these transporters are linked to various neurological disorders in humans (e.g., epilepsy, schizophrenia, depression, anxiety, and drug addiction). Furthermore, these transporters are the sites of action of various drugs of abuse [e.g., cocaine and amphetamines, including methylenedioxymethamphetamine (MDMA)] and are targets of several clinically approved drugs (e.g., desipramine, tiagabine, nisoxetine, benztropine, and reserpine).

Pharmacological Significance: Neurotransmitter transporters in the SLC6, SLC17, and SLC18 families are primarily expressed in neurons of the central and peripheral nervous system as well as in neuroendocrine tissues. Some of these transporters are also found in many non-neuronal tissues, such as kidney, liver, and intestine. A principal role of neurotransmitter transporters of the SLC6 family, which are expressed on the plasma membrane, is sequestration of extracellular solutes. Members of the SLC17 and SLC18 transporter families are instead expressed on the membrane of secretory vesicles and are primarily involved in the transport of neurotransmitters from the cytosol into secretory vesicles. Many clinically used drugs and abused substances are inhibitors or substrates of the SLC6, SLC17, and SLC18 families of neurotransmitter transporters. In particular, antidepressant and antiepileptic drugs target these neurotransmitter transporters as part of their primary mechanism of action. Therefore, the SLC6, SLC17, and SLC18 transporter families play an important role in the efficacy of such drugs.

Endogenous and Xenobiotic Substrates/Inhibitors: See Table 3.

Functional Characteristics:

SLC6: Synaptic signaling is terminated by a rapid accumulation of neurotransmitters into presynaptic terminals. The reuptake occurs via a cotransporter system, with the energy for transmitter transport provided by the Na⁺ electrochemical gradient.

SLC17: This family of transporters is primarily driven by the electrical membrane potential but also by the pH gradient (i.e., proton exchange), and several members mediate the uptake of glutamate in light membrane vesicles.

SLC18: The vesicular monoamine transporters accumulate cytosolic monoamines into synaptic vesicles using the H⁺ gradient generated by the vacuolar H⁺ pump. This family of transporters is responsible for uptake of acetylcholine and biogenic amines into storage vesicles.

Summary of Data Submitted:

Size of sample set assayed: DAT, NET, GAT1, VMAT1, and VACHT: 494 chromosomes; VGLUT3: 552 chromosomes; VMAT2: 898 chromosomes

Number of gene regions assayed: 81

Total bases assayed: 21,671

Number of variant sites: 167

Polymerase chain reaction primers reported: 162

Footnotes

Supported by National Institutes of Health Grant GM61390

First published on December 2, 2005

Article, publication date, and citation information can be found at http://pharmrev.aspetjournals.org.

doi:10.1124/pr.58.1.3.

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