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© The Rockefeller University Press, 0021-9525/2000/4/379/ $5.00
The Journal of Cell Biology, Volume 149, Number 2, April 17, 2000 379-396

Original Article

A Phosphorylation Site Regulates Sorting of the Vesicular Acetylcholine Transporter to Dense Core Vesicles

David E. Krantzb,c, Clarissa Waitesa, Viola Oorschote, Yongjian Liub, Rachel I. Wilsond, Philip K. Tanb, Judith Klumpermane, and Robert H. Edwardsa,b,d
a Graduate Programs in Neuroscience, Cell Biology, and Biomedical Sciences, University of California at San Francisco School of Medicine, San Francisco, California 94143-0435
b Department of Neurology, University of California at San Francisco School of Medicine, San Francisco, California 94143-0435
c Department of Psychiatry, University of California at San Francisco School of Medicine, San Francisco, California 94143-0435
d Department of Physiology, University of California at San Francisco School of Medicine, San Francisco, California 94143-0435
e Department of Cell Biology, University Medical Center and Institute of Biomembranes, Utrecht University, 3584 CX Utrecht, The Netherlands

Correspondence to: Robert H. Edwards, UCSF School of Medicine, 513 Parnassus Avenue, San Francisco, CA 94143-0435. Tel:(415) 502-5687 Fax:(415) 502-5687 E-mail:edwards{at}itsa.ucsf.edu.

Vesicular transport proteins package classical neurotransmitters for regulated exocytotic release, and localize to at least two distinct types of secretory vesicles. In PC12 cells, the vesicular acetylcholine transporter (VAChT) localizes preferentially to synaptic-like microvesicles (SLMVs), whereas the closely related vesicular monoamine transporters (VMATs) localize preferentially to large dense core vesicles (LDCVs). VAChT and the VMATs contain COOH-terminal, cytoplasmic dileucine motifs required for internalization from the plasma membrane. We now show that VAChT undergoes regulated phosphorylation by protein kinase C on a serine (Ser-480) five residues upstream of the dileucine motif. Replacement of Ser-480 by glutamate, to mimic the phosphorylation event, increases the localization of VAChT to LDCVs. Conversely, the VMATs contain two glutamates upstream of their dileucine-like motif, and replacement of these residues by alanine conversely reduces sorting to LDCVs. The results provide some of the first information about sequences involved in sorting to LDCVs. Since the location of the transporters determines which vesicles store classical neurotransmitters, a change in VAChT trafficking due to phosphorylation may also influence the mode of transmitter release.

Key Words: neurotransmitter, kinase, trafficking, exocytosis, monoamine


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