The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine
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- Eiden, L.E., Schäfer, M.K., Weihe, E. et al. Pflugers Arch - Eur J Physiol (2004) 447: 636. doi:10.1007/s00424-003-1100-5
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The vesicular amine transporters (VATs) are expressed as integral proteins of the lipid bilayer membrane of secretory vesicles in neuronal and endocrine cells. Their function is to allow the transport of acetylcholine (by the vesicular acetylcholine transporter VAChT; SLC18A3) and biogenic amines (by the vesicular monoamine transporters VMAT1 and VMAT2; SLC18A1 and SLC18A2) into secretory vesicles, which then discharge them into the extracellular space by exocytosis. Transport of positively charged amines by members of the SLC18 family in all cases utilizes an electrochemical gradient across the vesicular membrane established by proton pumping into the vesicle via a vacuolar ATPase; the amine is accumulated in the vesicle at the expense of the proton gradient, at a ratio of one translocated amine per two translocated protons. The members of the SLC18 family have become important histochemical markers for chemical coding in neuroendocrine tissues and cells. The structural basis of their remarkable ability to transport positively charged amines against a very large concentration gradient, as well as potential disease association with impaired transporter function and expression, are under intense investigation.
KeywordsCholinergicAdrenergic/noradrenergicSerotoninergicHistaminergicAutonomic nervous systemPeripheral and central nervous system (PNS; CNS)NeuroendocrineMast cellAdrenal medullaBasophil cellsDendritic (Langerhans) cellsEndocrine tumorPancreatic beta cell (insulin cell)Platelet/thrombocyte
Discovery of the vesicular amine transporters (VATs)
SLC18—the vesicular monoamine/acetylcholine transporter (VMAT/VAChT) family (5HT 5-OH-tryptamine, SIF cell small, intensely fluorescent cell, GI gastrointestinal, EC enterochromaffin, ECL enterochromaffin-like, ChAT choline acetyltransferase)
Human gene name
Transport type/coupling ions*
Tissue distribution and cellular/subcellular expression
Link to disease
Human gene locus
Sequence accession ID
Splice variants and their specific features
5HT, dopamine, adrenaline, noradrenaline, histamine
Adrenal gland (medulla), sympathetic ganglia (SIF-cells), carotid body, skin (Merkel cells), GI tract (EC cells), Subcellular: large dense-core vesicles
SVAT. SVMT, VAT2 (MAT)
5HT, dopamine, adrenaline, noradrenaline, histamine
Brain (neurons), adrenal gland (medulla), sympathetic ganglia (neurons, SIF cells), carotid body, small and large intestine (neurons), stomach (neurons and ECL-cells), endocrine pancreas, basophils, mast cells, dendritic cells and platelets, Subcellular: large dense-core vesicles, small, dense-core vesicles, tuberovesicular structures and small synaptic (dopaminergic) vesicles
Cardiovascular, drug addiction 
Brain (neurons), peripheral nervous system (neurons), intestine (neurons), Subcellular: small synaptic vesicles
Myasthenic syndromes (ChAT only) 
R-type, (minor variant), V-type, (major variant)
Functional characteristics and structural information
VATs accumulate singly positively-charged amines into the relatively proton-impermeable acidic secretory vesicles at the expense of proton antiport through the transporter protein (protons are first accumulated in secretory vesicles via a vacuolar ATPase not physically associated with the transporter) with a two proton:one amine stoichiometry, and to a final substrate concentration of up to 500 mM, exceeding that found in the cytosol by 100-fold (ACh) to 10,000-fold (biogenic amines).
The VATs (SLC18 s) are members of a larger solute carrier family, the TEXANs (toxin extruding antiporters). This class of transporter is found in many microorganisms and confers resistance to antibiotics and antiseptics in bacteria and yeast [17, 31]. NorA, a quinolone resistance protein from Staphylococcus aureus, and Bmr, a multiple drug resistance protein from Bacillus subtilis, are the closest relatives of the mammalian proteins, with the highest degree of homology detected in the six N-terminal putative transmembrane domains (i.e. 28% identity between VMAT1/SCL181A and Bmr) [36, 37]. Recently, a family of small, multi-drug resistance proteins that also function as TEXANs has been characterized and employed by Schuldiner and colleagues as a model system for VAT transport function, in which the role of transmembrane domain-resident negatively charged amino acids in substrate transport can be examined in detail [18, 28].
As far as is known, all metazoans that have acetylcholine- and biogenic amine-containing secretory vesicles have VATs that are structurally well-conserved . Mammalian VMAT1s generally show greater than 80% overall sequence identity, as do mammalian VMAT2s, while hVMAT1 (SLC18A1) has only 60% sequence identity with hVMAT2 (SLC18A2), and hVMAT1 and hVMAT2 have about 40% sequence identity with hVAChT (SLC18A3). The hVATs are 12-transmembrane domain (TMD) proteins based on Kyte-Doolittle hydropathy analysis of their primary sequences [10, 13, 15], and 10-transmembrane domain proteins based on MAXHOM alignment using the "profile-fed neural network systems from Heidelberg" (PHD) program (http://dodo.cpmc.columbia.edu/predictprotein/) [8, 34, 35]. The 10-TMD model for VAT differs principally from the 12-TMD model in failing to assign TMDs II and IV to the membrane, and placing these residues instead in the vesicle lumen (TMD II containing the LFASKA motif) or in the cytoplasm (TMD IV containing the conserved LQGxGS motif). Physical evidence to distinguish between these two models is lacking. The brief physical description of the VATs below assumes that they have 12 TMDs, following the current literature.
All VATs contain aspartate (D) residues in TMDs I, VI, X, and XI. The VMAT aspartate residues in TMDs I, X, and XI are thought to be critical for substrate recognition  and transport [27, 39]. The aspartates in TMD X and XI of VAChT appear to be equally important for acetylcholine recognition and transport, while those in TMD IV (conserved among all known metazoan VAChTs) and TMD X are critical for vesamicol binding . The cytoplasmic C-terminus of all VATs contains sequences required for (potentially phosphorylation-dependent) trafficking to the correct vesicle type (small synaptic vesicles for VAChT and large dense-core vesicles for VMATs), for recycling via endocytosis, and for phosphorylation that may control other aspects of transporter function (see  for review and references).
Pharmacology and imaging
Pharmacologically and clinically important drugs that interact with the VATs include vesamicol (VAChT/SLC18A3) , tetrabenazine (VMAT2/SLC18A2) and reserpine (VMAT2 and VMAT1/SLC18A1) [19, 23]. These drugs block amine uptake by VAChT and VMATs, respectively, and have pharmacological effects consistent with abrogation of amine storage and neurotransmission. Importantly, labeled vesamicol and tetrabenazine analogs exist that have been used successfully in brain imaging of vesicular transporter protein density in diseases such as Parkinson's, schizophrenia, and Alzheimer's disease (see  for review and references). The human isoforms of VMAT1 (SLC18A1) and VMAT2 (SLC18A2) transport catecholamines and serotonin, and are inhibited by reserpine, equally well, but hVMAT2 transports histamine, and is blocked by tetrabenazine, much better than hVMAT1, and rodent VMAT isoforms (slc18a1 and slc18a2) also exhibit these differences [14, 15, 25].
Homozygous knock-out of VAChT leads to failure of cholinergic neurotransmission in C. elegans, and homozygous knock-out of VMAT (there is only one isoform in worms) leads to an egg-laying- and locomotion-defective phenotype similar to treatment with reserpine [1, 4]. Homozygous knock-out of VMAT2 in mice is lethal, but partially rescuable with amphetamine, which can release biogenic amines from nerve terminals via a non-exocytotic mechanism . Heterozygous knock-out of VMAT2 in mice shows a clear gene dosage effect, with a halving of dopamine, norepinephrine, and serotonin content in brain [16, 40, 43].
*Note added in proof: VMAT2 is expressed in human pancreatic endocrine cells containing insulin but absent from islet cells expressing glucagon, somatostatin or pancreatic polypeptide [Anlauf M, Eissele R, Schäfer MK-H, Eiden LE, Arnold R, Pauser U, Klöppel G, Weihe E (2003) Expression of the two isoforms of the vesicular monoamine transporter (VMAT1 and VMAT2) in the endocrine pancreas and pancreatic endocrine tumors. J Histochem Cytochem (In press)].