期刊
JOURNAL OF PHYSIOLOGY-LONDON
卷 593, 期 1, 页码 245-265出版社
WILEY
DOI: 10.1113/jphysiol.2014.284133
关键词
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资金
- National Health and Medical Research Council (NHMRC) [569680]
- Motor Neuron Disease Research Institute Australia
- University of Queensland
beta 2-laminin is a key mediator in the differentiation and formation of the skeletal neuromuscular junction. Loss of beta 2-laminin results in significant structural and functional aberrations such as decreased number of active zones and reduced spontaneous release of transmitter. In vitro beta 2-laminin has been shown to bind directly to the pore forming subunit of P/Q-type voltage-gated calcium channels (VGCCs). Neurotransmission is initially mediated by N-type VGCCs, but by postnatal day 18 switches to P/Q-type VGCC dominance. The present study investigated the changes in neurotransmission during the switch from N- to P/Q-type VGCC-mediated transmitter release at beta 2-laminin-deficient junctions. Analysis of the relationship between quantal content and extracellular calcium concentrations demonstrated a decrease in the calcium sensitivity, but no change in calcium dependence at beta 2-laminin-deficient junctions. Electrophysiological studies on VGCC sub-types involved in transmitter release indicate N-type VGCCs remain the primary mediator of transmitter release at matured beta 2-laminin-deficient junctions. Immunohistochemical analyses displayed irregularly shaped and immature beta 2-laminin-deficient neuromuscular junctions when compared to matured wild-type junctions. beta 2-laminin-deficient junctions also maintained the presence of N-type VGCC clustering within the presynaptic membrane, which supported the functional findings of the present study. We conclude that beta 2-laminin is a key regulator in development of the NMJ, with its loss resulting in reduced transmitter release due to decreased calcium sensitivity stemming from a failure to switch from N- to P/Q-type VGCC-mediated synaptic transmission.
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