The RhoA GTPase-Activating Protein DLC2 Modulates RhoA Activity and Hyperalgesia to Noxious Thermal and Inflammatory Stimuli

Deleted in liver cancer 2 (DLC2) is a novel Rho GTPase-activating protein that regulates RhoA activity. DLC2 is ubiquitously expressed in most tissues, including the brain, spinal cord and peripheral nerves, and is thought to be involved in actin cytoskeletal reorganization. Unlike DLC1-deficient mice, DLC2-deficient mice (DLC2 –/– ) are viable and without gross anatomical abnormalities. Interestingly, DLC2 –/– mice exhibit hyperalgesia to noxious thermal stimuli and inflammation-inducing chemicals, such as formalin and acetic acid. There was no difference in the structure or morphology of cutaneous or sural nerves between DLC2 +/+ and DLC2 –/– mice. However, sensory nerve conduction velocity in DLC2 –/– mice was significantly higher than that in DLC2 +/+ mice, whereas motor nerve conduction velocity was not affected. After formalin injection, DLC2 –/– mice showed increased RhoA activity in the spinal cord and an increased number of phosphorylated ERK1/2-positive cells. The inflammatory hyperalgesia in DLC2 –/– mice appeared to be mediated through the activation of RhoA and ERK1/2. Taken together, DLC2 plays a key role in pain modulation during inflammation by suppressing the activation of RhoA and ERK to prevent an exaggerated pain response, and DLC2 –/– mice provide a valuable tool for further understanding the regulation of inflammatory pain.