1. Department of Cell Biology and Anatomy, University of North Carolina, Chapel Hill, North Carolina 27599-7090, USA
2. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599-7090, USA
3. Department of Molecular and Cell Physiology, University of North Carolina, Chapel Hill, North Carolina 27599-7090, USA
4. Department of Physiology and Neurobiology, University of Connecticut, 75 North Eagleville Road, U-156, Storrs, Connecticut 06269, USA
5. Present address: Department of Molecular and Cell Biology, University of Connecticut, 75 North Eagleville Road, U-125, Storrs, Connecticut 06269, USA.

Correspondence to: Juliet Lee^1,2 Correspondence and requests for materials should be addressed to J.L. (e-mail: Email: jlee@uconnvm.uconn.edu).

Intracellular calcium regulates many of the molecular processes that are essential for cell movement¹. It is required for the production of actomyosin-based contractile forces^{2, 3, 4}, the regulation of the structure and dynamics of the actin cytoskeleton⁵,⁶, and the formation and disassembly of cell–substratum adhesions⁷,⁸. Calcium also serves as a second messenger in many biochemical signal-transduction pathways⁷. However, despite the pivotal role of calcium in motile processes, it is not clear how calcium regulates overall cell movement. Here we show that transient increases in intracellular calcium, [Ca²⁺]_i, during the locomotion of fish epithelial keratocytes, occur more frequently in cells that become temporarily 'stuck' to the substratum or when subjected to mechanical stretching. We find that calcium transients arise from the activation of stretch-activated calcium channels, which triggers an influx of extracellular calcium. In addition, the subsequent increase in [Ca²⁺]_i is involved in detachment of the rear cell margin. Thus, we have defined a mechanism by which cells can detect and transduce mechanical forces into biochemical signals that can modulate locomotion.