Downregulation of the taurine transporter TauT during hypo-osmotic stress in NIH3T3 mouse fibroblasts.
Bottom Line: Taurine influx is reduced following reduction in osmolarity, keeping the extracellular Na(+) concentration constant.TonEBP activity is unaltered, whereas TauT transcription as well as TauT activity are significantly reduced under hypo-osmotic conditions.Acute exposure to ROS reduces taurine uptake as a result of modulated TauT transport kinetics.
Affiliation: Department of Biology, Section of Cellular and Developmental Biology, University of Copenhagen, The August Krogh Building, Universitetsparken 13, 2100 Copenhagen Ø, Denmark.Show MeSH
Related in: MedlinePlus
Mentions: Figure 4 summarizes data and illustrates modulation of taurine uptake by TauT in NIH3T3 cells following osmotic stress. TauT transcription is generally assumed to follow TonEBP activity. This is also the case for TauT transcription under hyperosmotic conditions (Fig. 2). However, we find that under long-term hypo-osmotic exposure the downregulation of TauT transcription is not secondary to reduced TonEBP activity as (1) TonEBP activity is unaltered whereas TauT mRNA is reduced (Fig. 2) and (2) stimulation and hindrance of TonEBP activity by increased NOX4 expression do not correlate with TauT transcription level (Fig. 3). The lack of correlation between TonEBP activity and TauT transcription under hypo-osmotic conditions could indicate that TauT transcription is dependent on other transcription factors inactivated by hypo-osmolarity. Under hyperosmotic conditions, ROS generated from the mitochondria are reported to stimulate TonEBP transactivation via a hyper-osmotically induced transactivation domain (TAD) (Zhou et al. 2006), and we hypothesize that the primary effect of ROS on TonEBP-TAD is an increased sensitivity toward tonicity. In this scenario ROS stimulate TonEBP transactivation under conditions with high extracellular ion concentrations, whereas TonEBP transactivation is further suppressed by NOX4-generated ROS under conditions with low extracellular ion concentrations. Our current hypothesis is that ROS-mediated interference with TauT kinetics is only visible under conditions with very low Na+ concentrations, i.e., concentrations significantly lower than those observed under hypo-osmotic hyponatremia, but will have no effect on taurine transport under conditions with high or normal extracellular Na+ concentrations. The hypo-osmotically induced reduction in TauT mRNA will reduce TauT activity following prolonged osmotic stress. The reduction in cellular taurine content following hyponatremia is probably dominated by increased taurine leak, whereas more chronic conditions can involve the reduction in TauT mRNA.
Affiliation: Department of Biology, Section of Cellular and Developmental Biology, University of Copenhagen, The August Krogh Building, Universitetsparken 13, 2100 Copenhagen Ø, Denmark.