Abstract
Zinc (Zn) confers structure and catalytic functions to a number of enzymes and transcription factors, and its homeostasis is tightly controlled by Zn transporters (SLC39/ZIP: importers, SLC30/ZnT: exporters). Zn is an essential trace element, and its deficiency is associated with abnormal endocrine-system reactions leading to vertebral growth retardation and metabolic disorders. However, the molecular mechanisms by which Zn affects the endocrine system remain to be clarified. Here we examined the in vivo roles of SLC39A14, a member of the SLC39 family, by generating its deficient mice. The Slc39a14-knockout (KO) mice exhibit growth retardation accompanied by abnormal chondrocyte differentiation, reduced growth hormone production, and an impaired gluconeogenic program. We found that these phenotypes are attributable to impaired G-protein coupled receptor (GPCR)-mediated signaling, via the parathyroid hormone 1 receptor (PTH1R), growth hormone releasing hormone receptor (GHRHR), and glucagon receptor (GCGR), respectively, due to the degradation of cyclic adenosine monophosphate (cAMP) by the higher phosphodiesterase (PDE) activity in the Slc39a14-KO mice. Thus, the Zn transporter SLC39A14 is a new regulator for GPCR-mediated signaling for systemic growth.
