Endothelin-1 (ET-1) has been proven to activate two types of Ca2+-permeable nonselective cation channels (designated NSCC-1 and NSCC-2) and a store-operated Ca2+ channel (SOCC) in rabbit internal carotid artery vascular smooth muscle cells (ICA VSMCs). Ca2+ influx through these channels plays an essential role for ET-1-induced mitogenesis in ICA VSMCs. The purpose of the current study was to investigate the effects of Ca2+ influx on intracellular pathways of ET-1-induced mitogenesis in ICA VSMCs using receptor-operated Ca2+ channel blockers, SK&F 96365 and LOE 908. We focused on extracellular-signal regulated kinase 1 and 2 (ERK1/2) in this context. PD 98059, an inhibitor of mitogen-activated protein kinase kinase, abolished the ET-1-induced increase in ERK1/2 activity, but only partially suppressed the mitogenesis. ERK1/2 activation by ET-1 was partially suppressed in the absence of extracellular Ca2+. Moreover, based on the sensitivity to SK&F 96365 and LOE 908, Ca2+ influx through NSCC-1, NSCC-2 and SOCC plays essential roles in the extracellular Ca2+-dependent component of ERK1/2 activity. In addition, Ca2+ influx through these channels was also involved in the PD 98059-resistant component of ET-1-induced mitogenesis. These results indicate that (1) the ET-1-induced mitogenesis involves both ERK1/2-dependent and -independent mechanisms in ICA VSMCs (2), ERK1/2 activation by ET-1 involves a Ca2+ influx-dependent cascade as well as a Ca2+ influx-independent cascade (3), Ca2+ influx through NSCC-1, NSCC-2 and SOCC has important roles in the Ca2+ influx-dependent component of ERK1/2-dependent mitogenesis, and (4) Ca2+ influx through these channels also plays important roles in mitogenic pathways downstream of ERK1/2.