Identification of CaVß1 isoforms required for neuromuscular junction formation and maintenance

Four CaVß proteins (CaVß1 to CaVß4) are described as regulatory subunit of Voltage-gated Ca2+ channel (VGCC), each exhibiting expression patterns in excitable cells based on their function. While primarily recognized for their role in VGCC regulation, CaVßs have channel-independent activity and regulate gene expression. Among these, CaVß1 is expressed in skeletal muscle as different isoforms. The adult constitutive isoform, CaVß1D, is located at the triad, where it modulates CaV1 function in the Excitation-Contraction Coupling (ECC). Here, we further explored the less characterized CaVß1 isoforms, focusing on embryonic/perinatal variants, and their specific role in the neuromuscular systems at different stages of NMJ formation, maturation and maintenance. Our findings revealed that CaVß1 isoforms expression is regulated by differential activation of promoters during development. First, we identified CaVß1A, as expressed in embryonic and denervated adult mouse skeletal muscle, concomitantly to the known CaVß1E variant. Interestingly, nerve damage in adult muscle triggers a shift of promoter activation leading to re-expression of CaVß1 embryonic/perinatal Cacnb1A and Cacnb1E transcripts. In addition, we found that these embryonic/perinatal isoforms are involved in NMJ formation in aneural agrin-induced AChR clustering system on primary myotubes in vitro and that their early postnatal and adult expression is crucial for NMJ maturation/ maintenance. Altogether these data provide new major insights on knowledge of neuromuscular system homeostasis.