Calcium, which shows a back-to-front concentration gradient in migrating cells, so that the concentration is highest in the back, is also required for activation of proteins in the leading lamella. Wei et al. used real-time confocal microscopy to investigate the spatiotemporal organization of intracellular calcium in migrating embryonic lung fibroblasts in an effort to make sense of this apparent paradox. Consistent with previous studies, they observed a shallow back-to-front calcium concentration gradient; however, they also saw short-lived high-calcium microdomains, which they called “calcium flickers.” Flickers, which were not apparent in stationary fibroblasts, were most active at the leading lamella. They disappeared when cells were exposed to Ca2+-free medium or when stretch-activated cation channels (SACCs) were blocked with streptomycin or Gd3+. Flickers were responsive to mechanical stress; indeed, by combining patch-clamp analysis with confocal imaging, the authors showed that negative pressure elicited single-channel bursting concurrently with flickerlike signals. SACCs are members of the transient receptor potential (TRP) family of ion channels, and TRPM7 knockdown with RNAi—or its inhibition with Mg2+—largely abolished flicker activity. Pharmacological analysis, combined with RNAi, indicated that the Ca2+ signal mediated by TRPM7 was amplified by calcium release from the endoplasmic reticulum through the type 2 inositol 1,4,5-trisphosphate receptor. Flicker activity was accentuated by uniform exposure to the chemoattractant platelet-derived growth factor (PDGF); application of PDGF perpendicular to the direction of migration, which led to turning toward the PDGF source, also elicited increased flicker activity in the region of lamella facing the PDGF source. Moreover, molecular or pharmacological manipulation of the flicker signal elicited concurrent changes in turning and chemotaxis. The authors thus conclude that the spatiotemporal organization of high-calcium microdomains plays a critical role in fibroblast directional migration.
C. Wei, X. Wang, M. Chen, K. Ouyang, L.-S. Song, H. Cheng, Calcium flickers steer cell migration. Nature 457, 901–905 (2009). [PubMed]