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Calcium Influx and Release Cooperatively Regulate AChR Patterning and Motor Axon Outgrowth during Neuromuscular Junction Formation

Published on Jun 1, 2018in Cell Reports7.815
· DOI :10.1016/j.celrep.2018.05.085
Mehmet Mahsum Kaplan2
Estimated H-index: 2
,
Nasreen Sultana2
Estimated H-index: 2
+ 6 AuthorsBernhard E. Flucher37
Estimated H-index: 37
Abstract
Summary Formation of synapses between motor neurons and muscles is initiated by clustering of acetylcholine receptors (AChRs) in the center of muscle fibers prior to nerve arrival. This AChR patterning is considered to be critically dependent on calcium influx through L-type channels (CaV1.1). Using a genetic approach in mice, we demonstrate here that either the L-type calcium currents (LTCCs) or sarcoplasmic reticulum (SR) calcium release is necessary and sufficient to regulate AChR clustering at the onset of neuromuscular junction (NMJ) development. The combined lack of both calcium signals results in loss of AChR patterning and excessive nerve branching. In the absence of SR calcium release, the severity of synapse formation defects inversely correlates with the magnitude of LTCCs. These findings highlight the importance of activity-dependent calcium signaling in early neuromuscular junction formation and indicate that both LTCC and SR calcium release individually support proper innervation of muscle by regulating AChR patterning and motor axon outgrowth.
  • References (52)
  • Citations (2)
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References52
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#1Lei Li (Case Western Reserve University)H-Index: 10
#2Wen Cheng XiongH-Index: 53
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Synapses, the fundamental unit in neuronal circuits, are critical for learning and memory, perception, thinking, and reaction. The neuromuscular junction (NMJ) is a synapse formed between motoneuro...
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The neuromuscular synapse is a relatively large synapse with hundreds of active zones in presynaptic motor nerve terminals and more than ten million acetylcholine receptors (AChRs) in the postsynaptic membrane. The enrichment of proteins in presynaptic and postsynaptic membranes ensures a rapid, robust, and reliable synaptic transmission. Over fifty years ago, classic studies of the neuromuscular synapse led to a comprehensive understanding of how a synapse looks and works, but these landmark st...
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#1Anamika Dayal (Innsbruck Medical University)H-Index: 6
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Skeletal muscle excitation–contraction (EC) coupling is initiated by sarcolemmal depolarization, which is translated into a conformational change of the dihydropyridine receptor (DHPR), which in turn activates sarcoplasmic reticulum (SR) Ca2+ release to trigger muscle contraction. During EC coupling, the mammalian DHPR embraces functional duality, as voltage sensor and l-type Ca2+ channel. Although its unique role as voltage sensor for conformational EC coupling is firmly established, the conven...
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One of the earliest steps in the development of the neuromuscular junction (NMJ) is the pre-patterning of acetylcholine receptors (AChR) in the center of muscle fibers. This process has recently been proposed to depend on L-type calcium currents. But its feeble current properties make the skeletal muscle calcium channel (Cav1.1) a poor candidate for this function. Independently a new Cav1.1e splice variant with greatly distinct current properties has been described. But so far this channel lacke...
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Developing skeletal muscle fibers are intrinsically pre-patterned prior to motor neuron innervation. Chen and colleagues show that a functional skeletal muscle dihydropyridine receptor (DHPR) is required for muscle pre-patterning during neuromuscular junction development. DHPR is an L-type calcium channel and its regulation of muscle pre-patterning requires calcium influx.
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