ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading.

ZIP8 (SLC39A8) belongs to the ZIP family of metal-ion transporters. Among the ZIP proteins, ZIP8 is most closely related to ZIP14, which can transport iron, zinc, manganese, and cadmium. Here we investigated the iron transport ability of ZIP8, its subcellular localization, pH dependence, and regulation by iron. Transfection of HEK 293T cells with ZIP8 cDNA enhanced the uptake of (59)Fe and (65)Zn by 200 and 40%, respectively, compared with controls. Excess iron inhibited the uptake of zinc and vice versa. In RNA-injected Xenopus oocytes, ZIP8-mediated (55)Fe(2+) transport was saturable (K(0.5) of ∼0.7 µm) and inhibited by zinc. ZIP8 also mediated the uptake of (109)Cd(2+), (57)Co(2+), (65)Zn(2+) > (54)Mn(2+), but not (64)Cu (I or II). By using immunofluorescence analysis, we found that ZIP8 expressed in HEK 293T cells localized to the plasma membrane and partially in early endosomes. Iron loading increased total and cell-surface levels of ZIP8 in H4IIE rat hepatoma cells. We also determined by using site-directed mutagenesis that asparagine residues 40, 88, and 96 of rat ZIP8 are glycosylated and that N-glycosylation is not required for iron or zinc transport. Analysis of 20 different human tissues revealed abundant ZIP8 expression in lung and placenta and showed that its expression profile differs markedly from ZIP14, suggesting nonredundant functions. Suppression of endogenous ZIP8 expression in BeWo cells, a placental cell line, reduced iron uptake by ∼40%, suggesting that ZIP8 participates in placental iron transport. Collectively, these data identify ZIP8 as an iron transport protein that may function in iron metabolism.

Impact of comorbid migraine on the clinical course of bipolar disorder.

BACKGROUND: Recent evidence suggests an association between migraine and bipolar disorder (BD), although the impact of this association in the clinical course of BD is relatively unknown. OBJECTIVE: This study aimed to compare 2 groups of individuals with BD (with vs without comorbid migraine) and evaluate differences in severity of clinical course. METHODS: Three hundred thirty-nine adults with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-defined bipolar I or II disorder were enrolled and divided into 2 groups: with and without comorbid migraine. Demographic and clinical data were obtained using standardized interviews. RESULTS: Patients with comorbid migraines had more mood episodes, especially those with depressive polarity. In addition, comorbid migraine was associated with a higher prevalence of psychiatric and general medical comorbidities. Differences between the 2 groups in number of lifetime hospitalizations for depression/mania, rates of rapid cycling, and history of suicide attempts were not observed after Bonferroni correction. CONCLUSIONS: Comorbid migraine seems to be associated with poor outcomes in BD. Additional studies should be conducted to investigate shared vulnerabilities and pathophysiologic mechanisms as well as treatment optimization of both illnesses.