Calcium Channels Link the Muscle-Derived Synapse Organizer Laminin β2 to Bassoon and CAST/Erc2 to Organize Presynaptic Active Zones

被引:74
作者
Chen, Jie
Billings, Sara E.
Nishimune, Hiroshi [1 ]
机构
[1] Univ Kansas, Med Ctr, Dept Anat & Cell Biol, Sch Med, Kansas City, KS 66160 USA
基金
美国国家卫生研究院;
关键词
EATON-MYASTHENIC-SYNDROME; MOTOR-NERVE TERMINALS; POLYMERASE-CHAIN-REACTION; NEUROTRANSMITTER RELEASE; NEUROMUSCULAR-JUNCTION; CA2+ CHANNELS; MICE LACKING; SKELETAL-MUSCLE; DIFFERENTIAL EXPRESSION; VESICLE EXOCYTOSIS;
D O I
10.1523/JNEUROSCI.3771-10.2011
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Synapse formation requires the organization of presynaptic active zones, the synaptic vesicle release sites, in precise apposition to postsynaptic neurotransmitter receptor clusters; however, the molecular mechanisms responsible for these processes remain unclear. Here, we show that P/Q-type and N-type voltage-dependent calcium channels (VDCCs) play essential roles as scaffolding proteins in the organization of presynaptic active zones. The neuromuscular junction of double knock-out mice for P/Q-and N-type VDCCs displayed a normal size but had significantly reduced numbers of active zones and docked vesicles and featured an attenuation of the active-zone proteins Bassoon, Piccolo, and CAST/Erc2. Consistent with this phenotype, direct interactions of the VDCC beta 1b or beta 4 subunits and the active zone-specific proteins Bassoon or CAST/Erc2 were confirmed by immunoprecipitation. A decrease in the number of active zones caused by a loss of presynaptic VDCCs resembled the pathological conditions observed in the autoimmune neuromuscular disorder Lambert-Eaton myasthenic syndrome. At the synaptic cleft of double knock-out mice, we also observed a decrease of the synaptic organizer laminin beta 2 protein, an extracellular ligand of P/Q-and N-type VDCCs. However, the transcription level of laminin beta 2 did not decrease in double knock-out mice, suggesting that the synaptic accumulation of laminin beta 2 protein required its interaction with presynaptic VDCCs. These results suggest that presynaptic VDCCs link the target-derived synapse organizer laminin beta 2 to active-zone proteins and function as scaffolding proteins to anchor active-zone proteins to the presynaptic membrane.
引用
收藏
页码:512 / 525
页数:14
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