Cellular first responders: calcium and annexins partner to manage wound healing

We’ve all suffered a cut from a blade, some broken glass, or even a sheet of paper. The smallest of wounds can cause infections and become detrimental if they don’t heal, so luckily for most of us, our immune system steps in to do the job. Just as the immune system kicks off a cascade of events to heal a cut, an individual cell kicks off a cascade of signals to manage disruption to its cell membrane. However, the molecular mechanisms that underlie cellular wound healing are quite complex, and we don’t have a complete picture of the phenomenon. In a recent study published in the August issue of GENETICS, Mitsutoshi Nakamura and Susan M. Parkhurst flesh out additional details of the process.

In eukaryotic cells, a structural protein called actin forms the cytoskeleton that underlies the cell membrane. When the cell cortex (cytoskeleton and membrane) is wounded, vesicles are recruited to temporarily plug the opening, and a ring of actin filaments and myosin fibers assembles around the site to rapidly close the wound. After the wound closes, the patch job is removed, and the cytoskeleton and cell membrane are remodeled to their normal states. Actin remodeling requires the activity of the Rho family of small guanosine triphosphatases (GTPases), including the guanine nucleotide exchange factors RhoGEF2 and RhoGEF3.

One of the earliest events after a cell is wounded is a swift influx of calcium from the extracellular space into the cell. The uniform inflow of calcium across the wound site recruits specific factors to precise locations—but how this occurs is still an open question. We do know, however, that a group of proteins called annexins bind specific phospholipids in a calcium-dependent manner and play a conserved role in wound healing. The authors previously showed that annexin AnxB9 is rapidly recruited to wounds and plays a vital role in actin stabilization in the Drosophila cell wound model by recruiting RhoGEF2 to the site. Interestingly, they found that AnxB9 is not required for RhoGEF3 recruitment.

In the current study, Nakamura and Parkhurst show that two additional Drosophila annexins, AnxB10 and AnxB11, are also rapidly recruited to distinct sites around the wound within seconds of injury and that they, in turn, recruit RhoGEF2 and RhoGEF3. The three annexins at the center of their work must find their way to specific locations, and they have non-redundant functions in stabilizing the formation of the actomyosin ring around the wound, which sets the stage for RhoGTPase-mediated repair. The authors show that, while the repair process can begin under reduced-calcium conditions, it is inefficient and ultimately unsuccessful.

Calcium signals are widely known as a second messenger and are crucial for many processes. In addition to its impacts on wound healing, an imbalance in calcium homeostasis is found in cancer, muscular dystrophy, and diabetes. Understanding the dynamics of calcium-mediated annexin recruitment may inform the development of therapeutic strategies to enhance cellular repair mechanisms. For instance, targeting annexin functions or modulating calcium signaling pathways could offer new avenues for treating injuries and diseases characterized by impaired wound repair. Continued research in this area promises to unveil further nuances of this vital cellular process—with potential applications in regenerative medicine and beyond.