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The Journal of Neuroscience, October 29, 2003, 23(30):9697-9709

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Cellular/Molecular
Vesicular Localization and Activity-Dependent Trafficking of Presynaptic Choline Transporters

Shawn M. Ferguson,¹ Valentina Savchenko,² Subbu Apparsundaram,³ Melissa Zwick,³ Jane Wright,² Craig J. Heilman,⁴ Hong Yi,⁴ Allan I. Levey,⁴ and Randy D. Blakely^1,2

¹Neuroscience Graduate Program, Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee 37232, ²Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, ³Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Kentucky 40536, and ⁴Department of Neurology and Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia 30322

Presynaptic synthesis of acetylcholine (ACh) requires a steady supply of choline, acquired by a plasma membrane, hemicholinium-3-sensitive (HC-3) choline transporter (CHT). A significant fraction of synaptic choline is recovered from ACh hydrolyzed by acetylcholinesterase (AChE) after vesicular release. Although antecedent neuronal activity is known to dictate presynaptic CHT activity, the mechanisms supporting this regulation are unknown. We observe an exclusive localization of CHT to cholinergic neurons and demonstrate that the majority of CHTs reside on small vesicles within cholinergic presynaptic terminals in the rat and mouse brain. Furthermore, immunoisolation of presynaptic vesicles with multiple antibodies reveals that CHT-positive vesicles carry the vesicular acetylcholine transporter (VAChT) and synaptic vesicle markers such as synaptophysin and Rab3A and also contain acetylcholine. Depolarization of synaptosomes evokes a Ca²⁺-dependent botulinum neurotoxin C-sensitive increase in the V_max for HC-3-sensitive choline uptake that is accompanied by an increase in the density of CHTs in the synaptic plasma membrane. Our study leads to the novel hypothesis that CHTs reside on a subpopulation of synaptic vesicles in cholinergic terminals that can transit to the plasma membrane in response to neuronal activity to couple levels of choline re-uptake to the rate of ACh release.

Key words: choline; transport; hemicholinium-3; synaptic vesicle; acetylcholine; VAChT

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Received July 30, 2003; revised September 10, 2003; accepted September 10, 2003.

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