To elucidate the function of M6a, which is a neuron-specific membrane glycoprotein of the brain and possesses putative phosphorylation sites for protein kinase C (PKC), we established rat M6a cDNA expression vector-transfected PC12 cells. These transfectants exhibited high susceptibilities to nerve growth factor (NGF) for neuronal differentiation. Interestingly, we found that Ca2+ influx in these transfectants was significantly augmented by the treatment of NGF, but not epidermal growth factor (EGF), which stimulates PC12 cell growth. NGF-dependent augmentation of Ca2+ influx was detected within 3 h and severely inhibited by EGTA- and PKC-specific inhibitors. Anti-M6 antibody suppressed both NGF-triggered Ca2+ influx and neuronal differentiation. These results support the idea that M6a implicates in neuronal differentiation as a novel Ca2+ channel gated selectively by phosphorylation with PKC in the downstream of NGF signaling pathway. (C) 2002 Elsevier Science (USA). All rights reserved.