In fact, considerable evidence indicates that Zn transporters are involved in regulating a variety of intracellular signaling pathways in CYT 11387 JAK inhibitor animals, from flies to vertebrates. In addition, Zn is reported to act as a neurotransmitter or rather, as an allosteric regulator for a Zn-sensing receptor, and as an intracellular signaling molecule. Somatic growth, which affects body size, is regulated by endogenous and systemic factors, such as nutrients, hormones, and growth factors. The production of growth hormone in the pituitary gland and of insulin-like growth factor in the liver are the main endocrine influences on somatic growth. GH and IGF-I regulate longitudinal bone growth by WZ8040 controlling endochondral ossification, a defined sequence of events underlying chondrocyte differentiation in the growth plate. Aberrant Zn homeostasis is associated with vertebrate growth retardation and metabolic disorders. In particular, Zn deficiency causes dwarfism with reductions in the circulating GH and IGF-I concentrations, and decreased growth-plate width, which is correlated with reduced cellular Zn content. Intriguingly, the growth retardation cannot be reversed by maintaining circulating levels of GH or IGF-I through exogenous administration in Zn-deficient animals. These findings collectively suggest that Zn��s uptake into cells and the subsequent intracellular Zn accumulation affect the hormone signaling cascade required for GH production and chondrocyte differentiation. Since the endocrine system consists of a complex group of glands involved in growth and metabolism, its perturbation can broadly affect human health, and it is important to elucidate the mechanisms underlying the early stages of endocrine disorders. However, the molecules responsible for Zn homeostasis have been elusive, and how Zn affects the intracellular signaling that regulates growth-related endocrine processes has been little studied. Our current study demonstrated that a Zn transporter, SLC39A14, controls GPCR-mediated signaling by maintaining the basal cAMP level and suppressing PDE activity. Our results showed that SLC39A14 is a novel endogenous regulator for systemic growth and energy homeostasis, and its role may provide a mechanism for the Zn-mediated regulation of endocrine signaling. PTHrP-PTH1R signaling plays an important role in the endochondral ossification process, in which it blocks the premature hypertrophic differentiation of proliferative chondrocytes. We concluded that SLC39A14 positively regulates PTHrP-PTH1R signaling based on the following findings. The morphology of the Slc39a14-KO growth plate featured accelerated hypertrophy, characterized by the elongated pHZ and HZ, similar to observations in genetically manipulated-Pth1r mice. The Slc39a14-KO growth plate showed increased expression levels of the hypertrophic markers Ihh and Col10a1. PTH1R signaling is reported to inhibit their expression levels, consistent with the observation of elongated pHZ and HZ in the Slc39a14-KO mice. Slc39a14-KO chondrocytes possessed a lower potential for PTH1R signal transduction.