Smase D Activates Voltage-Gated Cation Channels

Voltage-gated ion channels generate electric impulses in nerve, muscle and endocrine cells. These channels open in response to membrane depolarization. Previously studies from our group show that extracellular application of sphingomyelinase (SMase) D shifts the G-V curve of voltage-gated K+ channels in the hyperpolarized direction, thereby activating the channels in hyperpolarized potentials where they otherwise remain deactivated. SMase D hydrolyzes the phospholipid sphingomyelin which is primarily present in the outer leaflet of cell membranes. In doing so, it removes the positively charged choline group of sphingomyelin. Enzymatic removal of the positively charged choline groups makes it energetically easier for the positively charged voltage sensor to move outwardly, assuming an activated conformation. We have recently found that extracellular application of SMase D also shifts the conductance-voltage (G-V) relation of voltage-gated Na+ and Ca2+ channels in the hyperpolarized direction. Thus, SMase D apparently activates all three major classes of voltage-gated cation channels at hyperpolarized potentials where they otherwise remain closed.