GPR55‐dependent and ‐independent ion signalling in response to lysophosphatidylinositol in endothelial cells

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Abstract
Background and purpose:  The glycerol‐based lysophospholipid lysophosphatidylinositol (LPI) is an endogenous agonist of the G‐protein‐coupled receptor 55 (GPR55) exhibiting cannabinoid receptor‐like properties in endothelial cells. To estimate the contribution of GPR55 to the physiological effects of LPI, the GPR55‐dependent and ‐independent electrical responses in this cell type were investigated.Experimental approach:  Applying small interference RNA‐mediated knock‐down and transient overexpression, GPR55‐dependent and ‐independent effects of LPI on cytosolic free Ca2+ concentration, membrane potential and transmembrane ion currents were studied in EA.hy296 cells.Key results:  In a GPR55‐dependent, GDPβS and U73122‐sensitive manner, LPI induced rapid and transient intracellular Ca2+ release that was associated with activation of charybdotoxin–sensitive, large conductance, Ca2+‐activated, K+ channels (BKCa) and temporary membrane hyperpolarization. Following these initial electrical reactions, LPI elicited GPR55‐independent long‐lasting Na+ loading and a non‐selective inward current causing sustained membrane depolarization that depended on extracellular Ca2+ and Na+ and was partially inhibited by Ni2+ and La3+. This inward current was due to the activation of a voltage‐independent non‐selective cation current. The Ni2+ and La3+‐insensitive depolarization with LPI was prevented by inhibition of the Na/K‐ATPase by ouabain.Conclusions and implications:  LPI elicited a biphasic response in endothelial cells of which the immediate Ca2+ signalling depends on GPR55 while the subsequent depolarization is due to Na+ loading via non‐selective cation channels and an inhibition of the Na/K‐ATPase. Thus, LPI is a potent signalling molecule that affects endothelial functions by modulating several cellular electrical responses that are only partially linked to GPR55.