Cloning and characterization of the choline acetyltransferase structural gene (cha-1) from C. elegans

Alfonso, Aixa; Grundahl, Kiely; McManus, John; Rand, James B.

doi:10.1523/jneurosci.14-04-02290.1994

Cited by 78 publications

(57 citation statements)

References 41 publications

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“…Animals homozygous for this mutation are viable, and their growth and development appear to be normal, although they are slightly long and thin. Since cholinergic neurotransmission is essential for viability in C. elegans (Alfonso et al 1993(Alfonso et al , 1994, we conclude that the CHO-1 protein is not essential for cholinergic function.…”

Section: Resultsmentioning

confidence: 79%

“…The relatively mild phenotype of cho-1 mutants was therefore surprising, since cholinergic neurotransmission is essential for viability in C. elegans (Alfonso et al 1993(Alfonso et al , 1994. Clearly, in the absence of cho-1 function, choline for ACh synthesis must be supplied in other ways, either through other transporters, or by de novo synthesis.…”

Section: Resultsmentioning

confidence: 99%

“…The mild phenotypes of cho-1 null mutants are somewhat surprising since null mutations in other cholinergic genes in C. elegans, such as choline acetyltransferase (cha-1) or , result in early larval lethality (Alfonso et al 1993(Alfonso et al , 1994. Clearly, cho-1 function is not essential for cholinergic signaling in C. elegans.…”

Section: Discussionmentioning

confidence: 99%

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

Mullen

Mathews

et al. 2007

Genetics

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The cho-1 gene in Caenorhabditis elegans encodes a high-affinity plasma-membrane choline transporter believed to be rate limiting for acetylcholine (ACh) synthesis in cholinergic nerve terminals. We found that CHO-1 is expressed in most, but not all cholinergic neurons in C. elegans. cho-1 null mutants are viable and exhibit mild deficits in cholinergic behavior; they are slightly resistant to the acetylcholinesterase inhibitor aldicarb, and they exhibit reduced swimming rates in liquid. cho-1 mutants also fail to sustain swimming behavior; over a 33-min time course, cho-1 mutants slow down or stop swimming, whereas wildtype animals sustain the initial rate of swimming over the duration of the experiment. A functional CHO-1TGFP fusion protein rescues these cho-1 mutant phenotypes and is enriched at cholinergic synapses. Although cho-1 mutants clearly exhibit defects in cholinergic behaviors, the loss of cho-1 function has surprisingly mild effects on cholinergic neurotransmission. However, reducing endogenous choline synthesis strongly enhances the phenotype of cho-1 mutants, giving rise to a synthetic uncoordinated phenotype. Our results indicate that both choline transport and de novo synthesis provide choline for ACh synthesis in C. elegans cholinergic neurons.

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Section: Resultsmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

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

Mullen

Mathews

et al. 2007

Genetics

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“…3d). eat-2 encodes an ionotropic ACh receptor that is expressed in the MC-pharyngeal muscle neuron junction 30 ; thus, an eat-2 null mutation blocks cholinergic transmission from the MC to the pharyngeal muscles 31 ; cha-1 encodes a choline acetyltransferase that synthesizes the neurotransmitter ACh 32 and a cha-1 mutation results in reduced ACh. To test if tmc-1 and eat-2 act in the same pathway, we made an eat-2(ad1113); tmc-1(ok1859) double mutant and found that 39% (n ¼ 102) develop into adults at 4 d.p.h.…”

Section: Tmc-1 Functions To Retard Growth On Cemmmentioning

confidence: 99%

TMC-1 attenuates C. elegans development and sexual behaviour in a chemically defined food environment

et al. 2015

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Although diet affects growth and behaviour, the adaptive mechanisms that coordinate these processes in non-optimal food sources are unclear. Here we show that the C. elegans tmc-1 channel, which is homologous to the mammalian tmc deafness genes, attenuates development and inhibits sexual behaviour in non-optimal food, the synthetic CeMM medium. In CeMM medium, signalling from the pharyngeal MC neurons and body wall muscles slows larval development. However, in the non-standard diet, mutation in tmc-1 accelerates development, by impairing the excitability of these cells. The tmc-1 larva can immediately generate ATP when fed CeMM, and their fast development requires insulin signalling. Our findings suggest that the tmc-1 channel indirectly affects metabolism in wild-type animals. In addition to regulating the development, we show that mutating tmc-1 can relax diet-induced inhibition of male sexual behaviour, thus indicating that a single regulator can be genetically modified to promote growth rate and reproductive success in new environments.

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“…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 .…”

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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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Cloning and characterization of the choline acetyltransferase structural gene (cha-1) from C. elegans

Cited by 78 publications

References 41 publications

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

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

TMC-1 attenuates C. elegans development and sexual behaviour in a chemically defined food environment

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

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