The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine

Abstract

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.

Characterization of Human SLC4A10 as an Electroneutral Na/HCO3 Cotransporter (NBCn2) with Cl– Self-exchange Activity

“…Using sharp Cl Ϫ -selective microelectrodes, we found that the mean intracellular [Cl Ϫ ] of all six populations of oocytes, measured with the oocytes exposed to the ND96 solution, is ϳ40 mM ( Table 1, column 2). This value, which is similar to that reported by others for oocytes (32,33), is considerably higher than the equilibrium value of 23 mM (computed using the mean measured V m of Ϫ37 mV) 8 Fig. 9, A-C, and summarized in Fig.…”

“…the SLC18 family of vesicular amine transporters; for a review, see Ref. 8), thereby influencing neuronal excitability (9,10), synaptic transmission (for a review, see Ref. 11), and other parameters.…”

Action potentials and amphetamine release antipsychotic drug from dopamine neuron synaptic VMAT vesicles

“…Amphetamines are VMAT substrates and can induce DA release from DA-containing vesicles either by acting as weak bases to reduce the vesicular pH gradient or by inducing VMAT-mediated exchange with luminal DA (14)(15)(16)(17)(18)(19). VMAT-mediated exchange can only occur with two VMAT substrate molecules (20). Therefore, to test whether exchange could occur with CYAM, the effect of the VMAT inhibitor reserpine on punctate accumulation of CYAM in the striatum was determined.…”

“…3 B and C) and the function of VMAT, which transports two luminal protons out of the vesicle lumen for every monovalently charged substrate molecule transported into the vesicle (20). Because amphetamines are VMAT substrates, upon acute application, their transport into vesicles will produce countertransport of protons out of vesicles (i.e., because VMAT is a monoamine-proton antiporter).…”

Systematic investigation of genetic variability in 111 human genes—implications for studying variable drug response

“…VMAT1 is responsible for the peripheral vesicular storage and restorage of released catecholamines, serotonin and histamine. 19 This exchange is located in a highly conserved N-myristoylation site (determined with PROSITE 12 ), which Previous studies have discussed the advantages of htSNPs. 15,20 Among 98 of the 111 resequenced gene loci, the use of htSNPs would reduce by about a third the genotyping effort required to capture more than 80% of total haplotype diversity of coding regions for the European population.…”