Ca²⁺ influx through L-type Ca²⁺ channels controls the trailing tail contraction in growth factor-induced fibroblast cell migration

Growth factor-induced cell migration underlies various physiological and pathological processes. The mechanisms by which growth factors regulate cell migration are not completely understood. Although intracellular elevation of Ca²⁺ is known to be critical in cell migration, the source of this Ca²⁺ elevation and the mechanism by which Ca²⁺ modulates this process in fibroblast cells are not well defined. Here we show that increase of cellular Ca²⁺ through Ca²⁺ influx, rather than Ca²⁺ release from intracellular stores, is essential for growth factor-induced fibroblast cell migration. Voltage-gated L-type Ca²⁺ channels, previously known to exist in excitable cells such as neurons and muscle cells, are shown here to be present in fibroblasts as -well. Furthermore, these channels are responsible for the Ca²⁺ influx. L-type Ca ²⁺ channel inhibitors block growth factor-induced Ca²⁺ influx and fibroblast cell migration. One mechanism by which Ca²⁺ signals control cell migration is to regulate the contraction of the trailing edge of migrating fibroblasts; this process is controlled by the small GTPase Rho in fast migrating cells such as leukocytes. Downstream of Ca²⁺, both calmodulin and myosin light chain kinase, but not calcineurin, are involved leading to phosphorylation of the myosin light chain at the trailing end. Thus, trailing edge contraction is critically regulated by Ca²⁺ influx through L-type Ca²⁺ channels in growth factor-induced fibroblast cell migration.