Mechanisms of conotoxin inhibition of N-type (Cav2.2) calcium channels

► N-type (Cav2.2) VGCCs are involved in nociception and are a pain target. ► ω- and α-Conotoxins inhibit N-type VGCCs and can be developed as novel analgesics. ► ω-Conotoxins directly bind to and block Cav2.2 channels. ► Analgesic α-conotoxins inhibit N-type VGCCs via G protein-coupled GABAB receptors. ► Docking models suggest α-conotoxin Vc1.1 binding sites between GABAB ectodomains.