Voltage-gated calcium channels (VGCC) are osmosensitive. To test the hypothesis that this property of VGCCs stems from their susceptibility to alterations in the mechanical properties of the bilayer, we use native VGCCs in pituitary cells and reversibly perturb the bilayer with lipids that alter bilayer stress, i.e. cone-shaped lysophospholipids (LPLs). LPLs of different head group size and charge were used: lysophosphatidylcholine (LPC), lysophosphatidylinositol (LPI), lysophosphatidylserine (LPS) and lysophosphatidylethanolamine (LPE). Phosphatidylcholine (PC) and LPC (C6:0) were used as controls. We show that partition of both LPC and LPI into the membrane of pituitary cells suppressed L-type calcium channel currents (I_L). This suppression of I_L was slow in onset, reversible upon washout with BSA and associated with a depolarizing shift in activation (~ 8mV). In contrast to these effects of LPC and LPI on I_L, LPS, LPE, PC and LPC (C6:0) exerted minimal or insignificant effects. This difference may be attributed to the prominent conical shape of LPC and LPI compared to the shapes of LPS and LPE (which have smaller headgroups), and to PC (which is cylindrical). The similar effects of LPC and LPI on I_L, despite differences in the structure and charge of their headgroups, suggest a common lipid stress mechanism in their action. It is plausible that after slow incorporation of these cone-shaped lipids into the membrane of pituitary cells, bilayer mechanics and consequently lipid-protein interactions are different, in a way that suppresses calcium channel voltage sensor motion and thus positively shifts voltage dependence of activation.

This study was supported by the Israel Science Foundation Grants no. 826/04 and no. 1325/08 to I.N.