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The Journal of Neuroscience, June 7, 2006, 26(23):6200-6212; doi:10.1523/JNEUROSCI.5036-05.2006

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Cellular/Molecular
The Caenorhabditis elegans Choline Transporter CHO-1 Sustains Acetylcholine Synthesis and Motor Function in an Activity-Dependent Manner

Dawn Signor Matthies,¹ Paul A. Fleming,³ Don M. Wilkes,³ and Randy D. Blakely^1,2

¹Department of Pharmacology and ²Center for Molecular Neuroscience, Vanderbilt University School of Medicine, and ³Department of Electrical Engineering and Computer Science, Vanderbilt University, Nashville, Tennessee 37232-8548

Correspondence should be addressed to Dr. Randy D. Blakely, Suite 7140, Medical Research Building III, Center for Molecular Neuroscience, Nashville, TN 37232-8548. Email: randy.blakely{at}vanderbilt.edu

Cholinergic neurotransmission supports motor, autonomic, and cognitive function and is compromised in myasthenias, cardiovascular diseases, and neurodegenerative disorders. Presynaptic uptake of choline via the sodium-dependent, hemicholinium-3-sensitive choline transporter (CHT) is believed to sustain acetylcholine (ACh) synthesis and release. Analysis of this hypothesis in vivo is limited in mammals because of the toxicity of CHT antagonists and the early postnatal lethality of CHT–/– mice (Ferguson et al., 2004). In Caenorhabditis elegans, in which cholinergic signaling supports motor activity and mutant alleles impacting ACh secretion and response can be propagated, we investigated the contribution of CHT (CHO-1) to facets of cholinergic neurobiology. Using the cho-1 promoter to drive expression of a translational, green fluorescent protein-CHO-1 fusion (CHO-1:GFP) in wild-type and kinesin (unc-104) mutant backgrounds, we establish in the living nematode that the transporter localizes to cholinergic synapses, and likely traffics on synaptic vesicles. Using embryonic primary cultures, we demonstrate that CHO-1 mediates hemicholinium-3-sensitive, high-affinity choline uptake that can be enhanced with depolarization in a Ca²⁺-dependent manner supporting ACh synthesis. Although homozygous cho-1 null mutants are viable, they possess 40% less ACh than wild-type animals and display stress-dependent defects in motor activity. In a choline-free liquid environment, cho-1 mutants demonstrate premature paralysis relative to wild-type animals. Our findings establish a requirement for presynaptic choline transport activity in vivo in a model amenable to a genetic dissection of CHO-1 regulation.

Key words: choline; acetylcholine; transporter; C. elegans; CHT; CHO-1

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Received Nov. 25, 2005; revised April 27, 2006; accepted April 28, 2006.

Correspondence should be addressed to Dr. Randy D. Blakely, Suite 7140, Medical Research Building III, Center for Molecular Neuroscience, Nashville, TN 37232-8548. Email: randy.blakely{at}vanderbilt.edu

This article has been cited by other articles:

				P. W. McDonald, S. L. Hardie, T. N. Jessen, L. Carvelli, D. S. Matthies, and R. D. Blakely Vigorous Motor Activity in Caenorhabditis elegans Requires Efficient Clearance of Dopamine Mediated by Synaptic Localization of the Dopamine Transporter DAT-1 J. Neurosci., December 19, 2007; 27(51): 14216 - 14227. [Abstract] [Full Text] [PDF]

				G. P. Mullen, E. A. Mathews, M. H. Vu, J. W. Hunter, D. L. Frisby, A. Duke, K. Grundahl, J. D. Osborne, J. A. Crowell, and J. B. Rand Choline Transport and de novo Choline Synthesis Support Acetylcholine Biosynthesis in Caenorhabditis elegans Cholinergic Neurons Genetics, September 1, 2007; 177(1): 195 - 204. [Abstract] [Full Text] [PDF]

				B. Wang, L. Yang, Z. Wang, and H. Zheng Amyolid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter PNAS, August 28, 2007; 104(35): 14140 - 14145. [Abstract] [Full Text] [PDF]

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