In skeletal muscle, the voltage-gated calcium channel (VGCC) CaV1.1 enables the coupling between the electrical activity of motor neurons and muscle contraction, following stimulation of acetylcholine receptors at the neuromuscular junction (NMJ). The activity and localisation of CaV1.1 are regulated by the CaVβ subunit. In addition to this function, CaVβ plays a role in modulating gene expression and is expressed in skeletal muscle in multiple isoforms.
In this French study involving researchers from the Sorbonne University Center of Research in Myology, Inserm and the Institute of Myology, the authors identified two embryonic/perinatal isoforms of CaVβ1 expressed at low levels in healthy adult muscle and at high levels following nerve injury. They also deciphered the epigenetic mechanism regulating their expression in embryonic and adult muscle and discovered their roles in the formation, maturation and maintenance of the NMJ.
The results show that:
- the expression of CaVβ1 isoforms is regulated during development by the differential activation of specific promoters,
- CaVβ1A is expressed in embryonic muscle and denervated adult muscle, in parallel with the CaVβ1E isoform described in a previous study by the same team.
- Nerve damage in adult muscle triggers a change in promoter usage, leading to the re-expression of the embryonic and perinatal transcripts Cacnb1A and Cacnb1E.
- Morphological and biochemical analyses have shown that these isoforms contribute to the organisation of acetylcholine receptor aggregates at the sarcolemma, which are necessary for the establishment of embryonic muscle innervation.
- Their expression is essential for the formation/maturation of th e NMJ during early postnatal development and for its long-term maintenance during adulthood.
These results highlight the importance of CaVβ1 in the development and homeostasis of the neuromuscular system.
