| First Author | Chand KK | Year | 2015 |
| Journal | J Physiol | Volume | 593 |
| Issue | 1 | Pages | 245-65 |
| PubMed ID | 25556799 | Mgi Jnum | J:227584 |
| Mgi Id | MGI:5701588 | Doi | 10.1113/jphysiol.2014.284133 |
| Citation | Chand KK, et al. (2015) Loss of beta2-laminin alters calcium sensitivity and voltage-gated calcium channel maturation of neurotransmission at the neuromuscular junction. J Physiol 593(1):245-65 |
| abstractText | KEY POINTS: Neuromuscular junctions from beta2-laminin-deficient mice exhibit lower levels of calcium sensitivity. Loss of beta2-laminin leads to a failure in switching from N- to P/Q-type voltage-gated calcium channel (VGCC)-mediated transmitter release that normally occurs with neuromuscular junction maturation. The motor nerve terminals from beta2-laminin-deficient mice fail to up-regulate the expression of P/Q-type VGCCs clusters and down-regulate N-type VGCCs clusters, as they mature. There is decreased co-localisation of presynaptic specialisations in beta2-laminin-deficient neuromuscular junctions as a consequence of lesser P/Q-type VGCC expression. These findings support the idea that beta2-laminin is critical in the organisation and maintenance of active zones at the neuromuscular junction via its interaction with P/Q-type VGCCs, which aid in stabilisation of the synapse. beta2-laminin is a key mediator in the differentiation and formation of the skeletal neuromuscular junction. Loss of beta2-laminin results in significant structural and functional aberrations such as decreased number of active zones and reduced spontaneous release of transmitter. In vitro beta2-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 beta2-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 beta2-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 beta2-laminin-deficient junctions. Immunohistochemical analyses displayed irregularly shaped and immature beta2-laminin-deficient neuromuscular junctions when compared to matured wild-type junctions. beta2-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 beta2-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. |
