Increased neuromuscular activity causes axonal defects and muscular degeneration

Lefebvre, Julie L.; Ono, Fumihito; Puglielli, C.; Seidner, Glen A.; Franzini‐Armstrong, Clara; Brehm, Paul; Granato, Michael

doi:10.1242/dev.01123

Cited by 64 publications

(70 citation statements)

References 83 publications

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“…S3). Furthermore, in the zebrafish-muscle AChR, mutating (only) the two α1-subunit leucines at this position to proline slows down deactivation by a factor of ∼4 (28).…”

Section: Resultsmentioning

confidence: 99%

Mutations that stabilize the open state of the Erwinia chrisanthemi ligand-gated ion channel fail to change the conformation of the pore domain in crystals

González-Gutiérrez

Lukk

Agarwal

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The determination of structural models of the various stable states of an ion channel is a key step toward the characterization of its conformational dynamics. In the case of nicotinic-type receptors, different structures have been solved but, thus far, these different models have been obtained from different members of the superfamily. In the case of the bacterial member ELIC, a cysteamine-gated channel from Erwinia chrisanthemi, a structural model of the protein in the absence of activating ligand (and thus, conceivably corresponding to the closed state of this channel) has been previously generated. In this article, electrophysiological characterization of ELIC mutants allowed us to identify pore mutations that slow down the time course of desensitization to the extent that the channel seems not to desensitize at all for the duration of the agonist applications (>20 min). Thus, it seems reasonable to conclude that the probability of ELIC occupying the closed state is much lower for the ligand-bound mutants than for the unliganded wild-type channel. To gain insight into the conformation adopted by ELIC under these conditions, we solved the crystal structures of two of these mutants in the presence of a concentration of cysteamine that elicits an intracluster open probability of >0.9. Curiously, the obtained structural models turned out to be nearly indistinguishable from the model of the wild-type channel in the absence of bound agonist. Overall, our findings bring to light the limited power of functional studies in intact membranes when it comes to inferring the functional state of a channel in a crystal, at least in the case of the nicotinicreceptor superfamily.electrophysiology | structure-function T he use of bacterial and archaeal ion channels as models of the structure and function of their eukaryotic counterparts has become one of the mainstays of ion-channel biophysics. It seems to us that this practice is particularly well justified whenever the use of noneukaryotic channels facilitates experiments that are otherwise too difficult or too cumbersome to perform. A clear case in point is the determination of structural models of these membrane proteins using X-ray crystallography.One of the main goals of direct structural approaches as applied to ion channels is to determine what these proteins look like in their different functional states. Assuming that all of these conformations can form well-diffracting crystals, the problem is reduced to finding the conditions under which the occupancy of each particular state is maximized. In general, for well-characterized ion channels, the experimental maneuvers that are needed to favor or disfavor at least some of these different conformations are known. For example, in the case of (wild-type) neurotransmitter-gated channels, the binding of the natural neurotransmitter strongly stabilizes the desensitized state (e.g., ref. 1), whereas the absence of neurotransmitter or the binding of a competitive antagonist keeps the channel mostly closed (2, 3). Similarly, mut...

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“…S3). Furthermore, in the zebrafish-muscle AChR, mutating (only) the two α1-subunit leucines at this position to proline slows down deactivation by a factor of ∼4 (28).…”

Section: Resultsmentioning

confidence: 99%

Mutations that stabilize the open state of the Erwinia chrisanthemi ligand-gated ion channel fail to change the conformation of the pore domain in crystals

González-Gutiérrez

Lukk

Agarwal

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Before establishing terminal synapses with their final muscle targets, migrating motor axons form en passant synaptic contacts with myotomal muscle in zebrafish embryos. In twister AChR mutants, neuromuscular transmission is prolonged at these synapses, giving rise to aberrant motor axon trajectories as well as muscular degeneration (23). In Caenorhabditis elegans muscle cells appear to be required for formation of presynaptic varicosities by innervating motoneurons (24).…”

mentioning

confidence: 99%

Activity-dependent neurotransmitter-receptor matching at the neuromuscular junction

Borodinsky

Spitzer

2007

Proc. Natl. Acad. Sci. U.S.A.

109

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Signaling in the nervous system requires matching of neurotransmitter receptors with cognate neurotransmitters at synapses. The vertebrate neuromuscular junction is the best studied cholinergic synapse, but the mechanisms by which acetylcholine is matched with acetylcholine receptors are not fully understood. Because alterations in neuronal calcium spike activity alter transmitter specification in embryonic spinal neurons, we hypothesized that receptor expression in postsynaptic cells follows changes in transmitter expression to achieve this specific match. We find that embryonic vertebrate striated muscle cells normally express receptors for glutamate, GABA, and glycine as well as for acetylcholine. As maturation progresses, acetylcholine receptor expression prevails. Receptor selection is altered when early neuronal calcium-dependent activity is perturbed, and remaining receptor populations parallel changes in transmitter phenotype. In these cases, glutamatergic, GABAergic, and glycinergic synaptic currents are recorded from muscle cells, demonstrating that activity regulates matching of transmitters and their receptors in the assembly of functional synapses.

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“…In two such lines this has been shown to result from prolonged synaptic current decay producing sustained contractions on both sides of the tail. In the line ache slowed synaptic current results from the lack of muscle acetylcholinesterase (Behra et al, 2002), whereas in the twister line prolongation results from a mutation in the pore of the AChR ␣ subunit (Lefebvre et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Acetylcholine Receptors Direct Rapsyn Clusters to the Neuromuscular Synapse in Zebrafish

Ono¹,

Mandel²,

Brehm³

2004

J. Neurosci.

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Clustering of nicotinic muscle acetylcholine receptors (AChRs) requires association with intracellular rapsyn, a protein with an intrinsic ability to self-cluster. Previous studies on sofa potato (sop), an AChR null line of zebrafish, have suggested that AChRs may play an active role in subsynaptic localization of rapsyn clusters. To test this proposal directly, we identified and cloned the gene responsible for the sop phenotype and then attempted to rescue subsynaptic localization of the receptor-rapsyn complex in mutant fish. sop contains a leucine to proline mutation at position 28, near the N terminus of the zebrafish AChR ␦ subunit. Transient expression of mutant ␦ subunit in sop fish was unable to restore surface expression of muscle AChRs. In contrast, expression of wild-type ␦ subunit restored the ability of muscle to assemble surface receptors along with the ability of fish to swim. Most importantly, the ability of rapsyn clusters to localize effectively to subsynaptic sites also was rescued in large part. Our results point to direct involvement of the AChR molecule in restricting receptor-rapsyn clusters to the synapse.

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Increased neuromuscular activity causes axonal defects and muscular degeneration

Cited by 64 publications

References 83 publications

Mutations that stabilize the open state of the Erwinia chrisanthemi ligand-gated ion channel fail to change the conformation of the pore domain in crystals

Mutations that stabilize the open state of the Erwinia chrisanthemi ligand-gated ion channel fail to change the conformation of the pore domain in crystals

Activity-dependent neurotransmitter-receptor matching at the neuromuscular junction

Acetylcholine Receptors Direct Rapsyn Clusters to the Neuromuscular Synapse in Zebrafish

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