The ability of cells to sense and respond to physical stress is required for tissue homeostasis and normal development. In muscle, bone, tendon, periodontium, and the cardiovascular system, applied forces of physiological magnitude regulate cellular processes that are critical for normal tissue and organ functions, such as differentiation, proliferation, and migration (1). The periodontal ligament (PDL) 3 is a connective tissue interposed between the roots of teeth and the inner wall of the tooth-supporting bone (alveolar bone) socket. The PDL constitutively and iatrogenically receives mechanical stress, such as occlusal pressure and orthodontic forces, which have effects on the homeostasis of the PDL (2). Proper mechanical stress on teeth induces not only the proliferation and differentiation of PDL cells into osteoblasts and cementoblasts but also the synthesis and degradation of extracellular matrix (ECM) molecules (3). For example, during orthodontic tooth movement, two types of sites (tension sites and pressure sites) arise around the tooth through the orthodontic force. At the tension sites, the PDL is stretched, and the expressions of bone-related genes, such as osteocalcin (4) and bone sialoprotein (5), are up-regulated, such that bone formation is finally induced on the alveolar bone facing the tooth root (6). On the other hand, at the pressure sites, the PDL is compressed, and osteoclasts are activated. Consequently, resorption of the alveolar bone is induced. An orchestrated balance between bone formation and resorption controls tooth movement (7). In contrast, elimination of mechanical stress on teeth is known to cause atrophy of the PDL in vivo (8). Kaneko et al. (9) reported that loss of occlusal function by extraction of the antagonistic upper molars of rats caused atrophic changes in the PDL of the lower molars, such as narrowing of the space, disorientation of collagen fibers, and decreases in proteoglycans. These findings indicate that mechanical stress on teeth affects the remodeling of the PDL, cementum, and alveolar bone. Thus, it is important to clarify the physiological functions of mechanical stress on the PDL.To clarify the molecular basis of the mechanical stress-regulated PDL functions, we analyzed the gene expression profile of human PDL cells receiving tensile mechanical stress in vitro. Interestingly, an oligo-DNA chip analysis identified two glutamate signaling-associated genes, HOMER1 (homer homolog 1) and GRIN3A (glutamate receptor ionotropic N-methyl-D-aspartate 3A), among the up-regulated genes. L-Glutamate is the most abundant amino acid in the central nervous system and plays important roles in neurotransmission (10