Maintenance of Ca_V2.2 channel-current by PIP₂ unveiled by neomycin in sympathetic neurons of the rat.

Membrane lipids are key determinants in the regulation of voltage-gated ion channels. Phosphatidylinositol 4,5-bisphosphate (PIP₂), a native membrane phospholipid, has been involved in the maintenance of the current amplitude and in the voltage-independent regulation of voltage-gated calcium channels (VGCC). However, the nature of the PIP₂ regulation on VGCC has not been fully elucidated. This work aimed to investigate whether the interacting PIP₂ electrostatic charges may account for maintaining the current amplitude of Ca_V2.2 channels. Furthermore, we tested whether charge shielding of PIP₂ mimics the voltage-independent inhibition induced by M₁ muscarinic acetylcholine receptor (M₁R) activation. Therefore, neomycin, a polycation that has been shown to block electrostatic interactions of PIP_2, was intracellularly dialyzed in superior cervical ganglion (SCG) neurons of the rat. Consistently, neomycin time-dependently diminished the calcium current amplitude letting the channel exhibit the hallmarks of the voltage-independent regulation. These results support that interacting PIP₂ charges not only underly the maintenance of the channel-current but also that charge screening of PIP₂ by itself unveils the voltage-independent features of Ca_V2.2 channels in SCG neurons. Copyright © 2020 Elsevier Inc. All rights reserved.

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