Choline Transport and <i>de novo</i> Choline Synthesis Support Acetylcholine Biosynthesis in <i>Caenorhabditis elegans</i> Cholinergic Neurons

Mullen, Gregory P.; Mathews, Eleanor; Vu, Mai; Hunter, Jerrod W.; Frisby, Dennis L.; Duke, Angie; Grundahl, Kiely; Osborne, Jamie D.; Crowell, John A.; Rand, James B.

doi:10.1534/genetics.107.074120

Cited by 22 publications

(13 citation statements)

References 51 publications

(65 reference statements)

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“…CTL1 is, so far, the only member that demonstrates a choline transport function (24,26,27). In fact, evidence exists, from studies in yeast and nematodes, that suggests that paralogs of other members of SLC44A family are not choline transporters (28,29).…”

Section: Discussionmentioning

confidence: 99%

Molecular Identification and Functional Characterization of the Human Colonic Thiamine Pyrophosphate Transporter

Nabokina

Inoue

Subramanian

et al. 2014

Journal of Biological Chemistry

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Background: Human colonocytes possess a specific, high-affinity, and regulated carrier-mediated system for TPP uptake. Results: Human SLC44A4 protein functions as a TPP transporter. Conclusion: The SLC44A4-mediated TPP uptake system may play a role in the absorption of the microbiota-generated TPP in colon. Significance: Molecular identification of the colon-specific TPP uptake system is important for understanding the mechanisms of overall thiamine nutrition.

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Section: Discussionmentioning

confidence: 99%

Molecular Identification and Functional Characterization of the Human Colonic Thiamine Pyrophosphate Transporter

Nabokina

Inoue

Subramanian

et al. 2014

Journal of Biological Chemistry

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“…The SAB MNs are cholinergic, as determined by the expression of the evolutionarily conserved ACh pathway genes, unc-17 /VAChT [17, 18], cha-1 /ChAT [17] and cho-1 /ChT [19] (Figure 4A–B). We first examined whether the adoption of cholinergic neurotransmitter identity is temporally linked to synaptogenesis.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Coordination of Synaptogenesis and Neurotransmitter Signaling

et al. 2015

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SUMMARY During nervous system development, postmitotic neurons face the challenge of generating and structurally organizing specific synapses with appropriate synaptic partners. An important unexplored question is whether the process of synaptogenesis is coordinated with the adoption of specific signaling properties of a neuron. Such signaling properties are defined by the neurotransmitter system that a neuron uses to communicate with postsynaptic partners, by the neurotransmitter receptor type used to receive input from presynaptic neurons and, potentially, by other sensory receptors that activate a neuron. Elucidating the mechanisms that coordinate synaptogenesis, neuronal activation and neurotransmitter signaling in a postmitotic neuron represents one key approach to understand how neurons develop as functional units. Using the SAB class of Caenorhabditis elegans motor neurons as a model system, we show here that the phylogenetically conserved COE-type transcription factor UNC-3 is required for synaptogenesis. UNC-3 directly controls the expression of the ADAMTS-like protein MADD-4/Punctin, a presynaptically secreted synapse-organizing molecule that clusters postsynaptic receptors. UNC-3 also controls the assembly of presynaptic specializations and ensures the coordinated expression of enzymes and transporters that define the cholinergic neurotransmitter identity of the SAB neurons. Furthermore, synaptic output properties of the SAB neurons are coordinated with neuronal activation and synaptic input, as evidenced by UNC-3 also regulating the expression of ionotropic neurotransmitter receptors and putative stretch receptors. Our study shows how synaptogenesis and distinct, function-defining signaling features of a postmitotic neuron are hardwired together through coordinated transcriptional control.

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“…Swimming rates were measured using hermaphrodites raised at 20°as described previously . Acute response to 2 mM aldicarb (2-methyl-2- [methylthio]proprionaldehyde-O-[methylcarbamoyl]oxime; Chem Service, West Chester, PA) was measured as described previously (Lackner et al 1999;Mullen et al 2007). Statistical significance tests used the Student's t-test.…”

Section: Behavioral Assaysmentioning

confidence: 99%

Genetic Interactions Between UNC-17/VAChT and a Novel Transmembrane Protein in Caenorhabditis elegans

et al. 2012

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The unc-17 gene encodes the vesicular acetylcholine transporter (VAChT) in Caenorhabditis elegans. unc-17 reduction-offunction mutants are small, slow growing, and uncoordinated. Several independent unc-17 alleles are associated with a glycine-toarginine substitution (G347R), which introduces a positive charge in the ninth transmembrane domain (TMD) of UNC-17. To identify proteins that interact with UNC-17/VAChT, we screened for mutations that suppress the uncoordinated phenotype of UNC-17(G347R) mutants. We identified several dominant allele-specific suppressors, including mutations in the sup-1 locus. The sup-1 gene encodes a single-pass transmembrane protein that is expressed in a subset of neurons and in body muscles. Two independent suppressor alleles of sup-1 are associated with a glycine-to-glutamic acid substitution (G84E), resulting in a negative charge in the SUP-1 TMD. A sup-1 null mutant has no obvious deficits in cholinergic neurotransmission and does not suppress unc-17 mutant phenotypes. Bimolecular fluorescence complementation (BiFC) analysis demonstrated close association of SUP-1 and UNC-17 in synapse-rich regions of the cholinergic nervous system, including the nerve ring and dorsal nerve cords. These observations suggest that UNC-17 and SUP-1 are in close proximity at synapses. We propose that electrostatic interactions between the UNC-17(G347R) and SUP-1(G84E) TMDs alter the conformation of the mutant UNC-17 protein, thereby restoring UNC-17 function; this is similar to the interaction between UNC-17/ VAChT and synaptobrevin. C OORDINATED muscle contraction in both vertebrates and nematodes requires release of the neurotransmitter acetylcholine (ACh) from motor neurons. ACh is synthesized in motor neurons by the enzyme choline acetyltransferase (ChAT) and transported into synaptic vesicles by the vesicular ACh transporter (VAChT). Following transmitter release, cholinergic signaling is terminated primarily through the action of acetylcholinesterase (AChE), which hydrolyses the released ACh into choline and acetyl-CoA. In the nematode Caenorhabditis elegans, the ChAT and VAChT proteins are encoded by the cha-1 and unc-17 genes, respectively (Alfonso et al. , 1994b. Mutations that functionally eliminate either protein are lethal , while reduction-of-function mutations result in animals that are small, slow growing, uncoordinated, and resistant to AChE inhibitors such as aldicarb .The unc-17 missense mutation e245 replaces a glycine with an arginine (G347R) in the ninth transmembrane domain (TMD9) of the VAChT protein . Genetic screens designed to identify mutations that improve the locomotion of e245 homozygotes have identified several loci that suppress the deleterious effects of the VAChT G347R mutation. Sandoval et al. (2006) found that the sup-8 locus corresponds to the previously characterized snb-1 gene, which encodes the v-SNARE synaptobrevin. The single sup-8 allele is associated with a missense mutation that results in a charge alteration (I97D) in the TMD of synaptobrevin. T...

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Choline Transport and de novo Choline Synthesis Support Acetylcholine Biosynthesis in Caenorhabditis elegans Cholinergic Neurons

Cited by 22 publications

References 51 publications

Molecular Identification and Functional Characterization of the Human Colonic Thiamine Pyrophosphate Transporter

Molecular Identification and Functional Characterization of the Human Colonic Thiamine Pyrophosphate Transporter

Transcriptional Coordination of Synaptogenesis and Neurotransmitter Signaling

Genetic Interactions Between UNC-17/VAChT and a Novel Transmembrane Protein in Caenorhabditis elegans

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