Evoked Catecholamine Release from Sympathetic Nerve Terminals in Cardiac Slices

Abstract

Mutations in dysferlin cause Limb-Girdle and Miyoshi Muscular Dystrophy. Dysferlin is structurally related to Otoferlin, a protein involved in the calcium triggered release of neurotransmitters in cochlear hair cells. Dysferlin is a calcium-binding protein with a single membrane-spanning domain thought to be required for membrane wound repair. The specific function that dysferlin performs in wound healing is unknown. Here we report the activation of an intercellular signaling pathway in sea urchin embryos by membrane wounding that evokes calcium spikes in neighboring cells. This pathway was mimicked by ATP application, and inhibited by apyrase, cadmium, and omega-agatoxin IVA. Microinjection of dysferlin antisense morpholinos blocked this pathway; control morpholinos did not. Co-injection of mRNA encoding human dysferlin with the inhibitory morpholino rescued signaling activity. Our results indicate that membrane wounding triggers membrane depolarization, calcium influx through an agatoxin sensitive voltage-gated calcium channel, and ultimately the secretion of ATP. Moreover, dysferlin appears to mediate one of the essential steps in this signaling cascade.