Fig. 2.

Cellular functions modified by Ca²⁺-regulated alternative splicing. a Critical role of Ca²⁺-regulated NRX1 variants in synaptic maturation during development. Depolarization switches NRX1 post-synaptic ligand binding preference from NL-1B to Cbln1/GluD2 complex by inhibiting exon 20 (E20) inclusion in cerebellar neurons in an l-type Ca²⁺-channel dependent way. b Role of Ca²⁺-regulated AMPAR subunit isoforms in homeostatic synapse response. Inhibition of sodium channels with tetrodotoxin (TTX) or l-type Ca²⁺-channels with nifedipine results in the skipping of AMPAR subunits GluA1 and A2 Flip and inclusion of Flop exon in hippocampal CA1 neurons. Flip-included mRNA isoform GluA1i decays faster than GluA2i. Moreover, GluA1 turns over more rapidly than GluA2 protein variants in the endoplasmic reticulum, where AMPAR channel is assembled. Thus, TTX-induced activity blockage leads to the enrichment of newly synthesized GluA1o relative to GluA1i. GluA1o pairs preferentially with GluA2i variant producing GluA1o/A2i heterotetramer, which is associated with reduced depression of AMPAR-mediated excitatory post-synaptic potentials evoked by electrical stimulation of pre-synaptic neuron. For simplicity, nuclei of pre- (a) and post- (b) synaptic neurons are depicted close to synaptic membrane