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J Gen Physiol. 2018 May 7;150(5):671-682. doi: 10.1085/jgp.201711980. Epub 2018 Apr 17.

The ins and outs of vesicular monoamine transporters.

Author information

1
Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Hebrew University, Jerusalem, Israel dana.yaffe@mail.huji.ac.il.
2
Computational Structural Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD lucy.forrest@nih.gov.
3
Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Hebrew University, Jerusalem, Israel shimon.schuldiner@huji.ac.il.

Abstract

The H+-coupled vesicular monoamine transporter (VMAT) is a transporter essential for life. VMAT mediates packaging of the monoamines serotonin, dopamine, norepinephrine, and histamine from the neuronal cytoplasm into presynaptic vesicles, which is a key step in the regulated release of neurotransmitters. However, a detailed understanding of the mechanism of VMAT function has been limited by the lack of availability of high-resolution structural data. In recent years, a series of studies guided by homology models has revealed significant insights into VMAT function, identifying residues that contribute to the binding site and to specific steps in the transport cycle. Moreover, to characterize the conformational transitions that occur upon binding of the substrate and coupling ion, we have taken advantage of the unique and powerful pharmacology of VMAT as well as of mutants that affect the conformational equilibrium of the protein and shift it toward defined conformations. This has allowed us to identify an important role for the proton gradient in driving a shift from lumen-facing to cytoplasm-facing conformations.

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