Regulation of Glucose Transporter SGLT1 by Ubiquitin Ligase Nedd4‐2 and Kinases SGK1, SGK3, and PKB

Objectives : Serum‐ and glucocorticoid‐inducible kinase 1 (SGK1) inhibits the ubiquitin ligase neuronal cell expressed developmentally downregulated 4‐2 (Nedd4‐2), which retards the retrieval of the epithelial Na⁺ channel ENaC. Accordingly, SGK1 enhances ENaC abundance in the cell membrane. The significance of this effect is shown by an association of an E8CC/CT;I6CC polymorphism in the SGK1 gene with increased blood pressure. However, strong expression of SGK1 in enterocytes not expressing ENaC points to further functions of SGK1. This study was performed to test for regulation of Na⁺‐coupled glucose transporter 1 (SGLT1) by Nedd4‐2, SGK1, and/or the related kinases SGK3 and PKB. Additional studies searched for an association of the SGK1 gene with BMI. Research Methods and Procedures : mRNA encoding SGLT1, wild‐type Nedd4‐2, inactive ^C938SNedd4‐2, wild type SGK1, constitutively active ^S422DSGK1 or inactive ^K127NSGK1, wild‐type SGK3, and constitutively active ^T308DS473DPKB or inactive ^T308AS473APKB were injected into Xenopus oocytes, and glucose transport was quantified from glucose‐induced current (I_glc). BMI was determined in individuals with or without the E8CC/CT;I6CC polymorphism. Results: I_glc was significantly decreased by coexpression of Nedd4‐2 but not of ^C938SNedd4‐2. Coexpression of SGK1, ^S422DSGK1, SGK3, or ^T308DS473DPKB, but not of ^K127NSGK1 or ^T308AS473APKB, enhanced I_glc and reversed the effect of Nedd4‐2. SGK1 and SGK3 phosphorylated Nedd4‐2. Deletion of the SGK/PKB phosphorylation sites in Nedd4‐2 blunted the kinase effects. BMI was significantly (p < 0.008) greater in individuals with the E8CC/CT;I6CC polymorphism than in individuals without. Discussion : Overactivity of SGK1 may lead not only to excessive ENaC activity and hypertension but also to enhanced SGLT1 activity and obesity.     

In the Footprints of Our Ancestors: An Overview of the Hominid Track Record

Hominid footprints are particularly appealing and evocative of the living activity of our ancestors. The most famous and oldest (Late Pliocene, ca. 3.7 Ma) hominid footprints, from Laetoli in East Africa, have been attributed, with some uncertainly, to genus Homo or Australopithecus. The African track record also yields Early Pleistocene (～1.5 Ma) tracks attributable to Homo erectus. The only well-documented Middle Pleistocene tracks (age ～325,000-385,000 yrs) are reported from Italy and presumably represent a pre-Homo sapiens species.

The oldest Late Pleistocene tracks (～117,000 yrs), from southern Africa, may represent modern humans. However, the majority of Late Pleistocene sites are European, associated with caves in Romania, Greece, France and elsewhere, where hominid track preservation is often of high quality. Dates range from ～10,000 to ～62,000 BP Cavesite mammal tracks are almost exclusively those of carnivores, thus representing a distinctive underground ecology. Late Pleistocene open air sites are reported from widely scattered locations in Africa, Turkey, Tibet, Korea, Australia and even in the New World (Chile, Argentina and Mexico).

Early to Middle Holocene sites (> ～4,000 yrs BP) mainly occupy riparian, lacustrine, estuarine and littoral settings where the ichnofaunas are dominated by ungulates and shorebirds. Among these sites from England, Nicaragua, Argentina and Mexico and the United States, a few have been described in some detail. Younger Holocene sites are frequently associated with specified cultural periods (e.g., Neolithic, Bronze Age) or specific indigenous cultures, where supplemental archeological evidence may be directly associated with the footprint evidence.

At most surficial and some subterranean hominid tracksites, mammal and/or bird tracks are quite common and of use in creating a paleoecological picture of local faunas. The global distribution of human and hominid tracks is consistent with body fossil evidence and the record of archeological, cultural artifacts. However, in a few cases tracks suggest colonization of certain regions (Tibetan Plateau and the New World) earlier than previously thought. Tracks also give clues to behavior, age and health status of the trackmakers.     

Impaired IGF1R signaling in cells expressing longevity-associated human IGF1R alleles

Dampening of insulin/insulin-like growth factor-1 (IGF1) signaling results in the extension of lifespan in invertebrate as well as murine models. The impact of this evolutionarily conserved pathway on the modulation of human lifespan remains unclear. We previously identified two IGF1R mutations (Ala-37-Thr and Arg-407-His) that are enriched in Ashkenazi Jewish centenarians as compared to younger controls and are associated with the reduced activity of the IGF1 receptor as measured in immortalized lymphocytes. To determine whether these human longevity-associated IGF1R mutations affect IGF1 signaling, we engineered mouse embryonic fibroblasts (MEFs) expressing the different human IGF1R variants in a mouse Igf1r null background. The results indicate that MEFs expressing the human longevity-associated IGF1R mutations attenuated IGF1 signaling, as demonstrated by significant reduction in phosphorylation of both IGF1R and AKT after IGF1 treatment, in comparison with MEFs expressing the wild-type IGF1R. The impaired IGF1 signaling caused by the IGF1R mutations resulted in the reduced induction of the major IGF1-activated genes in MEFs, including EGR1, mCSF, IL3Rα, and TDAG51. Furthermore, the IGF1R mutations caused a delay in cell cycle progression after IGF1 treatment, indicating a dysfunctional physiological response to a cell proliferation signal. These results demonstrate that the human longevity-associated IGF1R variants are reduced-function mutations, implying that dampening of IGF1 signaling may be a longevity mechanism in humans.     

Development of gonadotropin-releasing hormone (GnRH) neuron regulation in the female rat

Summary 1. After reaching its final destination the GnRH neuronal network develops under the influence of both excitatory and inhibitory inputs.2. In the first 2 weeks of life, the immaturity of the GnRH neuronal system is reflected in sporadic unsynchronized bursts of the decapeptide, which determine the pattern of serum gonadotropin levels observed in female rats: high FSH levels and transient bursts of LH. The main inhibitory neuronal systems that operate in this period are the opioid and dopaminergic systems. A decrease in their inhibitory effectiveness may not be sufficient correctly to activate and synchronize the GnRH neuronal system.3. There is a concomitant increase in excitatory inputs, mainly noradrenaline, excitatory amino acids, and NPY, which increase the synthesis and release of GnRH at the beginning of the juvenile period and participate in the coupling of GnRH neural activity to the ongoing rhythmic activity of a hypothalamic circadian oscillator.4. The morphological changes of GnRH neurons which take place during the third and fourth weeks of life, and which are probably related to increasing estradiol levels, reflects the increasing complexity of the GnRH neuronal network, which establishes synaptic contacts to enable the expression of pulsatility and of the positive feedback of estradiol, both necessary components for the occurrence of puberty.