Sphingomyelinase D activates Native Voltage-Gated Ion Channels in Mammalian Cells

Abstract

Sphingomyelinase D (SMase D), a phospholipase present in the venom of Loxoceles spiders and also expressed by certain pathogenic bacteria, cleaves the choline headgroup from sphingomyelin. In Xenopus oocytes, SMase D treatment enables voltage sensors to mobilize at more negative potentials, consequently activating voltage-gated ion channels at more hyperpolarized voltages. If this effect is not an idiosyncrasy of the sphingomyelin-rich oocyte membrane or a function of aberrant membrane trafficking of over-expressed channels, SMase D may permit control of voltage-gated ion channel activity in non-excitable cells (e.g. lymphocytes). Hence, we tested the effect of SMase D on voltage-gated potassium (Kv) channels in mammalian cells. SMase D treatment left-shifts the conductance-voltage (G-V) relation of Kv channels heterologously expressed in CHO cells, resembling its effect in oocytes. Furthermore, SMase D also shifts the G-V curve of endogenously expressed Jurkat T-lymphocyte Kv1.3 channels in the hyperpolarized direction, activating channels at hyperpolarized potentials where they otherwise remain largely deactivated. Conceivably, modification of membrane lipids via either a physiological or pathological means can control or alter activity of voltage-gated ion channels.