Rapid and Reversible Effects of Activity on Acetylcholine Receptor Density at the Neuromuscular Junction in Vivo

Akaaboune, Mohammed; Culican, Susan M.; Turney, Stephen G.; Lichtman, Jeff W.

doi:10.1126/science.286.5439.503

Cited by 217 publications

(246 citation statements)

References 34 publications

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“…2). While the reduced lifetime of AChRs in the denervated muscles was anticipated from other studies (6,7,10,11), it showed remarkable similarity to the effects of interference with the actin cytoskeleton, PKA anchoring, myosin Va, and PKA function. Notably, injection of a single dose of CGRP blocked NMJ fragmentation upon denervation but not upon transfection with silMyoVa (Fig.…”

Section: Discussionsupporting

confidence: 64%

“…The high enrichment of AChRs in the postsynapse is regulated by accurate targeting and turnover of this receptor. Vesicular transport is employed for this purpose, using different routes of exocytosis, endocytosis, and recycling (7)(8)(9). We identified myosin Va as the first motor protein involved in AChR trafficking and have found it to facilitate its recycling (4).…”

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confidence: 99%

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Myosin Va cooperates with PKA RIα to mediate maintenance of the endplate in vivo

Röder¹,

Choi²,

Reischl

et al. 2010

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

108

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Myosin V motor proteins facilitate recycling of synaptic receptors, including AMPA and acetylcholine receptors, in central and peripheral synapses, respectively. To shed light on the regulation of receptor recycling, we employed in vivo imaging of mouse neuromuscular synapses. We found that myosin Va cooperates with PKA on the postsynapse to maintain size and integrity of the synapse; this cooperation also regulated the lifetime of acetylcholine receptors. Myosin Va and PKA colocalized in subsynaptic enrichments. These accumulations were crucial for synaptic integrity and proper cAMP signaling, and were dependent on AKAP function, myosin Va, and an intact actin cytoskeleton. The neuropeptide and cAMP agonist, calcitonin-gene related peptide, rescued fragmentation of synapses upon denervation. We hypothesize that neuronal ligands trigger local activation of PKA, which in turn controls synaptic integrity and turnover of receptors. To this end, myosin Va mediates correct positioning of PKA in a postsynaptic microdomain, presumably by tethering PKA to the actin cytoskeleton.cAMP | muscle | neuromuscular junction | microdomain | synaptic plasticity R ecently, myosin V motor proteins were found to be crucial for the plasticity of central and peripheral synapses by facilitating, respectively, the recycling of AMPA (1-3) and acetylcholine receptors (AChRs) (4). The neuromuscular junction (NMJ) is the synapse between motor neurons and skeletal muscle fibers. Even though it is formed during ontogenesis and then maintained over the years (5), half-lives (t 1/2 ) of a few days are typical for its protein constituents, such as the AChR (6). The high enrichment of AChRs in the postsynapse is regulated by accurate targeting and turnover of this receptor. Vesicular transport is employed for this purpose, using different routes of exocytosis, endocytosis, and recycling (7-9). We identified myosin Va as the first motor protein involved in AChR trafficking and have found it to facilitate its recycling (4). Down-regulation of myosin Va led to a reduced t 1/2 of AChRs (4) similar to pathological conditions, such as denervation (6, 10-13) or dystrophy (14). A shortened t 1/2 of AChRs accompanies morphological changes of the NMJ: while NMJs in mouse muscles are normally elliptic and pretzel-shaped (15), they elongate and fragment under pathological conditions (16,17).Previous studies have revealed a major role of cAMP signaling in controlling the t 1/2 of AChRs (12, 18). cAMP is formed upon activation of G protein-coupled receptors and mediates its effects mainly through protein kinase A (PKA). Notably, stimulation of cAMP synthesis rescued AChR lifetime in denervated (12,19) and dystrophic muscles (14). Several groups have described antagonistic functions of protein kinase C and PKA on AChR persistence and synaptic strength (18,20,21): although activation of protein kinase C destabilizes AChRs, PKA activity protects this receptor from such destabilization (18). In this context, the neuropeptide and cAMP agonist, α-calcitonin gene-rel...

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Section: Discussionsupporting

confidence: 64%

mentioning

confidence: 99%

Myosin Va cooperates with PKA RIα to mediate maintenance of the endplate in vivo

Röder¹,

Choi²,

Reischl

et al. 2010

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

108

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“…CHRN are bona fide transmembrane proteins and are composed of 5 subunits that are synthesized and assembled at the level of the endoplasmic reticulum, before they reach the postsynapstic membrane via Golgi apparatus and exocytic vesicles. 11,12 After their arrival at the membrane, CHRN can either persist there or get endocytosed in vesicular carriers 13,14 from where it might be either recycled back to the membrane or get degraded [15][16][17] in lysosomes. 18 While the expression of CHRN displays strong upregulation under muscle wasting conditions, 19,20 such as immobilization and denervation, its metabolic stability decreases at the same time, 10,21-23 implicating post-transcriptional regulation in CHRN turnover under stress.…”

Section: Introductionmentioning

confidence: 99%

Role of autophagy, SQSTM1, SH3GLB1, and TRIM63 in the turnover of nicotinic acetylcholine receptors

et al. 2013

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“…In both the central (O'Brien et al, 1998;Carroll et al, 1999a) and peripheral (Fambrough and Hartzell, 1972;Akaaboune et al, 1999;Sanes and Lichtman, 2001) nervous systems, alterations in synaptic transmission cause changes in postsynaptic receptor density. Such changes are important in many forms of synaptic plasticity, which lead to the strengthening or weakening of synaptic connections (Carroll et al, 1999b;Luscher et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Identification of Nicotinic Acetylcholine Receptor Recycling and Its Role in Maintaining Receptor Density at the Neuromuscular JunctionIn Vivo

Bruneau¹,

Sutter²,

Hume³

et al. 2005

J. Neurosci.

122

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In the CNS, receptor recycling is critical for synaptic plasticity; however, the recycling of receptors has never been observed at peripheral synapses. Using a novel imaging technique, we show here that nicotinic acetylcholine receptors (AChRs) recycle into the postsynaptic membrane of the neuromuscular junction. By sequentially labeling AChRs with biotin-bungarotoxin and streptavidin-fluorophore conjugates, we were able to distinguish recycled, preexisting, and new receptor pools at synapses in living mice. Time-lapse imaging revealed that recycled AChRs were incorporated into the synapse within hours of initial labeling, and their numbers increased with time. At fully functional synapses, AChR recycling was robust and comparable in magnitude with the insertion of newly synthesized receptors, whereas chronic synaptic activity blockade nearly abolished receptor recycling. Finally, using the same sequential labeling method, we found that acetylcholinesterase, another synaptic component, does not recycle. These results identify an activity-dependent AChRrecycling mechanism that enables the regulation of receptor density, which could lead to rapid alterations in synaptic efficacy.

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Rapid and Reversible Effects of Activity on Acetylcholine Receptor Density at the Neuromuscular Junction in Vivo

Cited by 217 publications

References 34 publications

Myosin Va cooperates with PKA RIα to mediate maintenance of the endplate in vivo

Myosin Va cooperates with PKA RIα to mediate maintenance of the endplate in vivo

Role of autophagy, SQSTM1, SH3GLB1, and TRIM63 in the turnover of nicotinic acetylcholine receptors

Identification of Nicotinic Acetylcholine Receptor Recycling and Its Role in Maintaining Receptor Density at the Neuromuscular JunctionIn Vivo

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