Semaphorin 3A growth cone collapse requires a sequence homologous to tarantula hanatoxin

Axonal guidance is key to the formation of neuronal circuitry. Semaphorin 3 A (Sema 3A; previously known as semaphorin ill, semaphorin D, and collapsin -1), a secreted subtype of the semaphorin family, is an important axonal gu idance molecule in vitro and in vivo. The molecular mechanisms of the repel lent activity of semaphorins are, however, poorly understood. We have now f ound that the secreted semaphorins contain a short sequence of high homolog y to hanatoxin, a tarantula K+ and Ca2+ ion channel blocker. Point mutation s in the hanatoxin-like sequence of Sema 3A reduce its capacity to repel em bryonic dorsal root ganglion axons. Sema 3A growth cone collapse activity i s inhibited by hanatoxin, general Ca2+ channel blockers, a reduction in ext racellular or intracellular Ca2+, and a calmodulin inhibitor, but not by K channel blockers. Our data support an important role for Ca2+ in mediating the Sema 3A response and suggest that Sema 3A may produce its effects by c ausing the opening of Ca2+ channels.