☆ 4.6 Article

Loss of β2-laminin alters calcium sensitivity and voltage-gated calcium channel maturation of neurotransmission at the neuromuscular junction

JOURNAL OF PHYSIOLOGY-LONDON (2015)

Journal

JOURNAL OF PHYSIOLOGY-LONDON

Volume 593, Issue 1, Pages 245-265

Publisher

WILEY

DOI: 10.1113/jphysiol.2014.284133

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Funding

National Health and Medical Research Council (NHMRC) [569680]
Motor Neuron Disease Research Institute Australia
University of Queensland

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Abstract

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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A cross-sectional study of ageing at the mouse neuromuscular junction and effects of an experimental therapeutic approach for dynapenia

Y. Li, M. Patel, J. Baroudi, M. Wu, S. Gatti, M. Liang, P. Wipf, Y. Badawi, Stephen D. Meriney

Summary: Despite previous efforts, the age-induced loss of muscle strength, known as dynapenia, remains a significant challenge with negative impacts on the quality of life in older individuals. Our study focused on the neuromuscular junction (NMJ) and revealed biphasic neurotransmission changes in male mice, with an initial increase followed by a later decrease, alongside structural alterations in the NMJ. We successfully used the therapeutic candidate GV-58 to mitigate age-induced reductions in transmitter release, resulting in improved muscle function.

JOURNAL OF PHYSIOLOGY-LONDON (2023)