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Eif2ak1  -  eukaryotic translation initiation factor 2...

Rattus norvegicus

Synonyms: Eukaryotic translation initiation factor 2-alpha kinase 1, HCR, Heme-controlled repressor, Heme-regulated eukaryotic initiation factor eIF-2-alpha kinase, Heme-regulated inhibitor, ...
 
 
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Disease relevance of Eif2ak1

  • Normoxic VO(2 max) (in ml. min(-1). kg(-1)) was 64.4 +/- 0.4 and 57.6 +/- 1.5 (P < 0.05), whereas VO(2 max) in hypoxia was 42.7 +/- 0.8 and 35.3 +/- 1.5 (P < 0.05) in HCR and LCR, respectively [1].
  • Mono-association with either Streptococcus mutans 6715 or Strep. faecalis ND547 produced extensive caries in caries-susceptible (HCS) rats and little or no caries in resistant (HCR) ones, but caries incidence did not relate to levels of agglutinating antibodies in serum or saliva [2].
 

High impact information on Eif2ak1

  • (i) Protein synthesis inhibition in a heme-deficient reticulocyte lysate is not due to the activation of an eIF-2 kinase (heme-regulated inhibitor), as is generally believed, but is due to degradation of p67 [3].
  • The heme-regulated inhibitor is present in an active form and possibly in equal amounts in both heme-deficient and heme-supplemented reticulocyte lysates but cannot phosphorylate eIF-2 alpha subunit because of the presence of p67 [3].
  • p67, a cellular glycoprotein, protects eIF2alpha from phosphorylation by inhibitory kinases such as double-stranded RNA dependent eIF2 kinase, PKR, and heme-controlled repressor and thus promotes protein synthesis in mammalian cells [4].
  • In rats given 20 mg/kg cocaine, behavior was more uniform across individuals, but still warranted separation into LCR/HCR categories [5].
  • In contrast, complex formation by an almost homogeneous eIF-2 preparation was unaffected by HCR: sensitivity to HCR was however restored by a factor which catalyses exchange of guanine nucleotides bound to eIF-2 [6].
 

Biological context of Eif2ak1

  • The predicted amino acid sequence of the kinase from rat brain shows 82% homology to rabbit reticulocyte HCR with the greatest variation concentrated in a central region of approximately 135 amino acids located between protein kinase subdomains IV and VI [7].
  • O(2) transport during maximal exercise was studied in rats bred for extremes of exercise endurance, to determine whether maximal O(2) uptake (VO(2 max)) was different in high- (HCR) and low-capacity runners (LCR) and, if so, which were the phenotypes responsible for the difference [1].
  • Peak normoxic maximum O(2) consumption and muscle O(2) conductance were previously reported to be 12 and 33% higher, respectively, in HCR, despite similar ventilation, arterial O(2) saturation, and a cardiac output that was <10% greater in HCR compared with LCR [8].
 

Anatomical context of Eif2ak1

  • Under identical experimental conditions, addition of partially purified heme-regulated inhibitor results in a complete disaggregation of polysomes [9].
  • To attempt to explain the difference in intrinsic (untrained) endurance running capacity in rats selectively bred over seven generations for either low (LCR) or high running capacity (HCR), the relationship among skeletal muscle capillarity, fiber composition, enzyme activity, and O(2) transport was studied [8].
  • Thus mitochondria from HCR rats exhibit enhanced mitochondrial sensitivity to creatine (i.e., the ability of creatine to decrease the Km for ADP) [10].
  • Total capillary and fiber number in the medial gastrocnemius were similar in HCR and LCR, but, because fiber area was 37% lower in HCR, the number of capillaries per unit area (or mass) of muscle was higher in HCR by 32% (P < 0.001) [8].
 

Associations of Eif2ak1 with chemical compounds

  • We propose that increased respiratory sensitivity to ADP in the presence of creatine can effectively increase muscle sensitivity to ADP during exercise (when creatine is increased) and may be, in part, a contributing factor for the increased running capacity in HCR rats [10].
  • The alpha subunit of eukaryotic protein synthesis initiation factor (eIF-2 alpha) is phosphorylated at a single serine residue (Ser51) by two distinct and well-characterized protein kinase, the haem-controlled repressor (HCR) and the double-stranded RNA-activated inhibitor (dsI) [11].
  • Limited tryptic digestion and subsequent cyanogen bromide treatment of rat liver eIF-2 phosphorylated by HCR yielded one major phosphopeptide [12].
  • These data also showed that the specificities of the two kinases were different from one another and from the specificities of two other protein kinases which recognise basic residues, cAMP-dependent protein kinase and protein kinase C. In histones, HCR phosphorylated only serine residues while dsI phosphorylated serine and threonine [11].
 

Analytical, diagnostic and therapeutic context of Eif2ak1

  • Based on phosphoamino acid analyses and gel filtration of tryptic fragments, dsI was capable of phosphorylating both 'sites' in clupeine Y1 and salmine A1, whereas HCR acted only on the N-terminal cluster of serines in these protamines [11].
  • As estimated from a speed-ramped treadmill exercise test to exhaustion (15 degrees slope; initial velocity of 10 m/min, increased 1 m/min every 2 min), HCR rats ran 10 times further (2,375+/-80 m) compared with LCR rats (238+/-12 m) [10].

References

  1. Determinants of maximal O(2) uptake in rats selectively bred for endurance running capacity. Henderson, K.K., Wagner, H., Favret, F., Britton, S.L., Koch, L.G., Wagner, P.D., Gonzalez, N.C. J. Appl. Physiol. (2002) [Pubmed]
  2. Antibody response and dental caries in the bacterium Streptococcus-mono-associated, caries-resistant and caries-susceptible rats. Peri, B.A. Arch. Oral Biol. (1987) [Pubmed]
  3. The eukaryotic initiation factor 2-associated 67-kDa polypeptide (p67) plays a critical role in regulation of protein synthesis initiation in animal cells. Ray, M.K., Datta, B., Chakraborty, A., Chattopadhyay, A., Meza-Keuthen, S., Gupta, N.K. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  4. Induction of apoptosis due to lowering the level of eukaryotic initiation factor 2-associated protein, p67, from mammalian cells by antisense approach. Datta, B., Datta, R. Exp. Cell Res. (1999) [Pubmed]
  5. Individual differences in cocaine-induced locomotor activity in rats: behavioral characteristics, cocaine pharmacokinetics, and the dopamine transporter. Gulley, J.M., Hoover, B.R., Larson, G.A., Zahniser, N.R. Neuropsychopharmacology (2003) [Pubmed]
  6. Regulation of binding of initiator tRNA to eukaryotic initiation factor eIF-2. Effects of the haem-controlled repressor on the kinetics of ternary complex formation. Proud, C.G., Clemens, M.J., Pain, V.M. FEBS Lett. (1982) [Pubmed]
  7. Cloning and characterization of cDNA encoding rat hemin-sensitive initiation factor-2 alpha (eIF-2 alpha) kinase. Evidence for multitissue expression. Mellor, H., Flowers, K.M., Kimball, S.R., Jefferson, L.S. J. Biol. Chem. (1994) [Pubmed]
  8. Selected contribution: skeletal muscle capillarity and enzyme activity in rats selectively bred for running endurance. Howlett, R.A., Gonzalez, N.C., Wagner, H.E., Fu, Z., Britton, S.L., Koch, L.G., Wagner, P.D. J. Appl. Physiol. (2003) [Pubmed]
  9. Some properties of a partially purified inhibitor(s) of protein synthesis from rat-liver mitochondria. Wu, J.M., Mosca, J., Suhadolnik, R.J., Ibrahim, N.G. Eur. J. Biochem. (1983) [Pubmed]
  10. Enhanced mitochondrial sensitivity to creatine in rats bred for high aerobic capacity. Walsh, B., Hooks, R.B., Hornyak, J.E., Koch, L.G., Britton, S.L., Hogan, M.C. J. Appl. Physiol. (2006) [Pubmed]
  11. The substrate specificity of protein kinases which phosphorylate the alpha subunit of eukaryotic initiation factor 2. Proud, C.G., Colthurst, D.R., Ferrari, S., Pinna, L.A. Eur. J. Biochem. (1991) [Pubmed]
  12. Structure and regulation of eukaryotic initiation factor eIF-2. Sequence of the site in the alpha subunit phosphorylated by the haem-controlled repressor and by the double-stranded RNA-activated inhibitor. Colthurst, D.R., Campbell, D.G., Proud, C.G. Eur. J. Biochem. (1987) [Pubmed]
 
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