ω-Phonetoxins inhibit voltage-gated calcium Ca2.2 ion channel splice isoforms of dorsal root ganglia.

Cell-specific alternative splicing of pre-mRNA generates functionally distinct voltage-gated Ca2.2 channels. Ca2.2 channels mediate the release of glutamate from nociceptor termini in the dorsal horn spinal cord and they are implicated in chronic pain. One alternatively spliced exon in , e37a, is highly expressed in dorsal root ganglia, relative to other regions of the nervous system, and it is particularly important in inflammatory hyperalgesia. Here we studied the effects of two ω-phonetoxins, PnTx3-4 and Phα1β, derived from the spider on Ca2.2 channel isoforms of dorsal root ganglia (Ca2.2 e37a and Ca2.2 e37b). Both PnTx3-4 and Phα1β are known to have analgesic effects in rodent models of pain and to inhibit Ca2.2 channels. Ca2.2 e37a and Ca2.2 e37b isoforms expressed in a mammalian cell line were inhibited by PnTx3-4 and Phα1β with similar potency and with similar timecourse, although Ca2.2 e37a currents were slightly, but consistently more sensitive to toxin inhibition compared to Ca2.2 e37b. The inhibitory effects of PnTx3-4 and Phα1β on Ca2.2-e37a and Ca2.2-e37b channels were voltage-dependent, and both occlude the inhibitory effects of ω-conotoxin GVIA, consistent with a common site of action. The potency of PnTx3-4 and Phα1β on both major splice isoforms in dorsal root ganglia constribute to understanding the analgesic actions of these ω-phonetoxins.