G protein-coupled receptors (GPCRs) have been implicated in lysophosphatidylethanolamine (LPE)-induced increases in intracellular Ca2+ ([Ca2+](i)), but in different cell types, this response may be dependent or independent of lysophosphatidic acid (LPA) GPCR. The effects of LPEs from Grifola frondosa on the neuronal differentiation and apoptosis of PC-12 neuronal cells have been previously reported. In the present study, the authors sought to identify the mechanism responsible for the effects of LPEs in PC-12 neuronal cells. LPE increase [Ca2+](i); concentration-dependently in PC-12 neuronal cells, but this LPE-induced [Ca2+](i); increase was less than that elicited by LPA. Studies using specific inhibitors showed that LPE-induced Ca2+ response was mediated via pertussis toxin-sensitive G(i/o) proteins, edelfosine-sensitive phospholipase C, and 2-APB-sensitive IP3 receptor and by Ca2+ influx across the cell membrane, and that this did not involve the conversion of LPE to LPA. Furthermore, LPE- and LPA-induced responses were found to show homologous and heterologous desensitization in PC-12 cells. VPC32183 and Ki16425 (antagonists of LPA(1) and LPA(3)) inhibited LPE-induced [Ca2+](i) increases. Furthermore, AM-095 (a specific inhibitor of LPA(1)) inhibited LPE-induced Ca2+ response completely in PC-12 cells. These findings indicate LPE increases [Ca2+](i) via a LPA(1)/G(i/o) proteins/phospholipase C/IP3/Ca2+ rise/Ca2+ influx pathway in PC-12 neuronal cells. (C) 2015 Elsevier Inc. All rights reserved.