Cloning and functional expression of a tetrabenazine sensitive vesicular monoamine transporter from bovine chromaffin granules

Howell, Mike; Shirvan, Anat; Stern‐Bach, Yael; Steiner‐Mordoch, Sonia; Strasser, Jane E.; Dean, Gary E.; Schuldiner, Shimon

doi:10.1016/0014-5793(94)80108-8

Cited by 61 publications

(31 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…VMAT2 from other species as well as VMAT1 show strong conservation of this sequence, supporting its significance (25,(51)(52)(53). In addition, many leucine-based motifs including those for VMAT2, VMAT1, and VAChT contain acidic residues at positions Ϫ4 or Ϫ5 relative to the di-leucine-like sequences (Table I).…”

Section: Endocytosis Of Synaptic Vesicle Transportersmentioning

confidence: 70%

A Leucine-based Motif Mediates the Endocytosis of Vesicular Monoamine and Acetylcholine Transporters

Tan¹,

Waites

Liu

et al. 1998

Journal of Biological Chemistry

109

158

View full text Add to dashboard Cite

Specific transport proteins mediate the packaging of neurotransmitters into secretory vesicles and consequently require targeting to the appropriate intracellular compartment. To identify residues in the neuronspecific vesicular monoamine transporter (VMAT2) responsible for endocytosis, we examined the effect of amino (NH 2 -) and carboxyl (COOH-)-terminal mutations on steady state distribution and internalization. Deletion of a critical COOH-terminal domain sequence (AKEEKMAIL) results in accumulation of VMAT2 at the plasma membrane and a 50% reduction in endocytosis. Site-directed mutagenesis shows that replacement of the isoleucine-leucine pair within this sequence by alanine-alanine alone reduces endocytosis by 50% relative to wild type VMAT2. Furthermore, the KEEKMAIL sequence functions as an internalization signal when transferred to the plasma membrane protein Tac, and the mutation of the isoleucine-leucine pair also abolishes internalization of this protein. The closely related vesicular acetylcholine transporter (VAChT) contains a similar di-leucine sequence within the cytoplasmic COOH-terminal domain that when mutated results in accumulation of VAChT at the plasma membrane. The VAChT di-leucine sequence also confers internalization when appended to two other proteins and in one of these chimeras, conversion of the di-leucine sequence to dialanine reduces the internalization rate by 50%. Both VMAT2 and VAChT thus use leucine-based signals for efficient endocytosis and as such are the first synaptic vesicle proteins known to use this motif for trafficking.

show abstract

Section: Endocytosis Of Synaptic Vesicle Transportersmentioning

confidence: 70%

A Leucine-based Motif Mediates the Endocytosis of Vesicular Monoamine and Acetylcholine Transporters

Tan¹,

Waites

Liu

et al. 1998

Journal of Biological Chemistry

109

158

View full text Add to dashboard Cite

show abstract

“…By analogy with other biologically active monoamines, it seems plausible that histamine enters the ECL cell secretory granule by means of a VMAT. However, the known members of this transporter family, VMATt (Liu et al 1992) and VMAT2 (Erickson et al 1992;Liu et al 1992;Krejci et al 1993;Surratt et al 1993;Howell et al 1994) (Hakanson, 1970), and the other major endocrine cell type, the D cell, has been reported not to possess amine-handling properties (Rubin & Schwartz, 1983, 1984. The relatively poor affinity for histamine of VMAT2 may not be critical in the histamine-rich ECL which, at least in rats, is essentially devoid of serotonin and catecholamines (Hakanson, 1970;Rubin & Schwartz, 1983, 1984 (Dimaline & Sandvik, 1991;Swarovsky et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Expression and regulation of a vesicular monoamine transporter in rat stomach: a putative histamine transporter.

Dimaline

Struthers

1996

The Journal of Physiology

View full text Add to dashboard Cite

1. Vesicular monoamine transporters (VMATs) translocate monoamines from the cytoplasm into secretory vesicles of endocrine cells and neurones, but they have limited affinity for histamine, and the identity of the vesicular transporter for this monoamine is uncertain. The aims of the present study were to characterize VMAT representatives in rat gastric corpus, and to determine if their expression was regulated by factors that modulate histamine biosynthesis. 2. Polymerase chain reaction (PCR) cloning using oligonucleotide primers to DNA sequences conserved within the VMAT family provided evidence for VMAT2, but not VMAT1 in rat gastric corpus. Northern analysis using a VMAT2 complementary RNA probe revealed a single 4 kb mRNA species in corpus endocrine cells.3.. In rats treated for up to 5 days with the H+-K+-ATPase inhibitor omeprazole, VMAT2, histidine decarboxylase and chromogranin A mRNA abundance in gastric corpus, and plasma gastrin concentrations increased progressively. Omeprazole also elevated VMAT2 expression in rats fasted for 48 h, but fasting alone, or refeeding fasted animals had no effect. 4. The results are consistent with a role for VMAT2 in the transport of histamine into enterochromaffin-like cell secretory vesicles, and with upregulation of the transporter to accommodate the increased histamine biosynthesis and secretion that accompanies achlorhydria.

show abstract

“…Somewhat surpisingly, the neuronal VMAT2 isoform has been found to be abundantly expressed in the bovine adrenal medulla (9)(10)(11). This observation suggested that important species differences may exist in the expression of the VMAT isoforms in endocrine organs and neural tissues.…”

mentioning

confidence: 98%

Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter.

Erickson

Schäfer

Bonner

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

412

389

View full text Add to dashboard Cite

A second isoform of the human vesicular monoamine transporter (hVMAT) has been cloned from a pheochromocytoma cDNA library. The contribution of the two transporter isoforms to monoamine storage in human neuroendocrine tissues was examined with isoform-specific polyclonal antibodies against hVMAT1 and hVMAT2. Central, peripheral, and enteric neurons express only VMAT2. VMAT1 is expressed exclusively in neuroendocrine, including chromaffin and enterochromaffin, cells. VMAT1 and VMAT2 are coexpressed in all chromaffin cells of the adrenal medulla. VMAT2 alone is expressed in histamine-storing enterochromaffin-like cells of the oxyntic mucosa of the stomach. The transport characteristics and pharmacology of each VMAT isoform have been directly compared after expression in digitonin-permeabilized fibroblastic (CV-1) cells, providing information about substrate feature recognition by each transporter and the role of vesicular monoamine storage in the mechanism of action of psychopharmacologic and neurotoxic agents in human. Serotonin has a similar affinity for both transporters. Catecholamines exhibit a 3-fold higher affinity, and histamine exhibits a 30-fold higher affinity, for VMAT2. Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2. N-methyl-4-phenylpyridinium, phenylethylamine, amphetamine, and methylenedioxymethamphetamine are all more potent inhibitors of VMAT2 than of VMAT1, whereas fenfluramine is a more potent inhibitor of VMAT1-mediated monamine transport than of VMAT2-mediated monoamine transport. The unique distributions of hVMAT1 and hVMAT2 provide new markers for multiple neuroendocrine lineages, and examination of their transport properties provides mechanistic insights into the pharmacology and physiology of amine storage in cardiovascular, endocrine, and central nervous system function.Storage of monoamines in secretory organelles of neurons, endocrine/paracrine cells, basophils, blood platelets, and mast cells is critical for their regulated, physiological secretion. Monoamine accumulation from the cytoplasm into storage organelles is mediated by vesicular monoamine transporters (VMATs) with an absolute dependence on a vacuolar ATPase-generated proton gradient to transport the cationic amine substrates into the storage organelle in exchange for protons (1).Recently, we cloned a VMAT (formerly named MAT) from a rat basophilic leukemia cell line (RBL-2H3) by functional expression of T7 promoter-driven cDNA sublibraries in CV-1 fibroblasts infected with T7 polymerase-expressing recombinant vaccinia virus (2). Permeabilization of the plasma membrane with digitonin provided the first demonstration that monoamine substrates could be directly accumulated by an intracellular compartment of nonneuroendocrine cells expressing this transporter in an ATP-dependent fashion that was sensitive to the specific inhibitors reserpine and tetrabenazine (TBZ). The mRNA for this transpor...

show abstract

Cloning and functional expression of a tetrabenazine sensitive vesicular monoamine transporter from bovine chromaffin granules

Cited by 61 publications

References 20 publications

A Leucine-based Motif Mediates the Endocytosis of Vesicular Monoamine and Acetylcholine Transporters

A Leucine-based Motif Mediates the Endocytosis of Vesicular Monoamine and Acetylcholine Transporters

Expression and regulation of a vesicular monoamine transporter in rat stomach: a putative histamine transporter.

Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter.

Contact Info

Product

Resources

About