CSTX-1, a toxin from the venom of the hunting spider Cupiennius salei, is a selective blocker of L-type calcium channels in mammalian neurons

Abstract The inhibitor cystine-knot motif identified in the structure of CSTX-1 from Cupiennius salei venom suggests that this toxin may act as a blocker of ion channels. Whole-cell patch-clamp experiments performed on cockroach neurons revealed that CSTX-1 produced a slow voltage-independent block of both mid/low- (M-LVA) and high-voltage-activated (HVA) insect Ca v channels. Since C. salei venom affects both insect as well as rodent species, we investigated whether Ca v channel currents of rat neurons are also inhibited by CSTX-1. CSTX-1 blocked rat neuronal L-type, but no other types of HVA Ca v channels, and failed to modulate LVA Ca v channel currents. Using neuroendocrine GH3 and GH4 cells, CSTX-1 produced a rapid voltage-independent block of L-type Ca v channel currents. The concentration–response curve was biphasic in GH4 neurons and the subnanomolar IC 50 values were at least 1000-fold lower than in GH3 cells. L-type Ca v channel currents of skeletal muscle myoballs and other voltage-gated ion currents of rat neurons, such as I Na(v) or I K(v) were not affected by CSTX-1. The high potency and selectivity of CSTX-1 for a subset of L-type channels in mammalian neurons may enable the toxin to be used as a molecular tool for the investigation of this family of Ca v channels.