Placental Anionic and Cationic Amino Acid Transporter Expression in Growth Hormone Overexpressing and Null IGF-II or Null IGF-I Receptor Mice

Matthews, J. C.; Beveridge, Mark; Dialynas, Emmanuel; Bartke, Andrzej; Kilberg, Michael S.; Novak, Donald A.

doi:10.1053/plac.1999.0421

Cited by 50 publications

(17 citation statements)

References 48 publications

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“…EAAT3 is not only expressed in neurons [28,[51][52][53][54][55][56][57], retinal ganglion cells [58] and glial cells [59,60] but is expressed in a wide variety of nonexcitable cells and non-neuronal tissues including blood platelets [61,62], heart [63], renal podocytes [64], epididymis [65], placenta [66,67] and blood-brain barrier [68].…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Glutamate Transporters by JAK2

Hosseinzadeh

Bhavsar²,

Sopjani³

et al. 2011

Cell Physiol Biochem

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The Janus-activated kinase-2 JAK2 is involved in the signaling of leptin and erythropoietin receptors and mediates neuroprotective effects of the hormones. In theory, JAK2 could be effective through modulation of the glutamate transporters, carriers accounting for the clearance of glutamate released during neurotransmission. The present study thus elucidated the effect of JAK2 on the glutamate transporters EAAT1, EAAT2, EAAT3 and EAAT4. To this end, cRNA encoding the carriers was injected into Xenopus oocytes with or without cRNA encoding JAK2 and glutamate transport was estimated from glutamate induced current (I_glu). I_glu was observed in Xenopus oocytes expressing EAAT1 or EAAT2 or EAAT3 or EAAT4, but not in water injected oocytes. Coexpression of JAK2 resulted in an increase of I_glu by 83% (EAAT1), 67% (EAAT2), 42% (EAAT3) and 126% (EAAT4). As shown for EAAT4 expressing Xenopus oocytes, the effect of JAK2 was mimicked by gain of function mutation ^V617FJAK2 but not by the inactive mutant ^K882EJAK2. Incubation with JAK2 inhibitor AG490 (40 µM) resulted in a gradual decrease of I_glu by 53%, 79% and 92% within 3, 6 and 24 hours. Confocal microscopy and chemiluminescence analysis revealed that JAK2 coexpression increased EAAT4 protein abundance in the cell membrane. Disruption of transcription did not appreciably modify the up-regulation of I_glu in EAAT4 expressing oocytes. The decay of I_glu following inhibition of carrier insertion with brefeldin A was similar in oocytes expressing EAAT4 + JAK2 and oocytes expressing EAAT4 alone, indicating that JAK2 did not appreciably affect carrier retrieval from the membrane. In conclusion, JAK2 is a novel powerful regulator of glutamate transporters and thus participates in the protection against excitotoxicity.

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Section: Discussionmentioning

confidence: 99%

Regulation of the Glutamate Transporters by JAK2

Hosseinzadeh

Bhavsar²,

Sopjani³

et al. 2011

Cell Physiol Biochem

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“…3b). The fall in System A activity is accompanied by reduced placental expression of the non-imprinted Slc38a2 gene and by changes in expression of the System X-AG and System Y+ amino acid transporter proteins in the junctional and labyrinthine zones [20, 24]. In addition, the reduced glycogen content of the complete Igf2 null placenta may affect glucose availability, although the mechanisms by which glycogen stored in the basal part of the junctional zone can influence feto-placental glucose metabolism remain unknown [25].…”

Section: The Igf2 Gene and Placental Nutrient Transfer Capacitymentioning

confidence: 99%

Imprinted Genes, Placental Development and Fetal Growth

Fowden

Sibley²,

Reik³

et al. 2006

Horm Res Paediatr

223

176

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In mammals, imprinted genes have an important role in feto-placental development. They affect the growth, morphology and nutrient transfer capacity of the placenta and, thereby, control the nutrient supply for fetal growth. In particular, the reciprocally imprinted Igf2–H19 gene complex has a central role in these processes and matches the placental nutrient supply to the fetal nutrient demands for growth. Comparison of Igf2P0 and complete Igf2 null mice has shown that interplay between placental and fetal Igf2 regulates both placental growth and nutrient transporter abundance. In turn, epigenetic modification of imprinted genes via changes in DNA methylation may provide a mechanism linking environmental cues to placental phenotype, with consequences for development both before and after birth. Changes in expression of imprinted genes, therefore, have major implications for developmental programming and may explain the poor prognosis of the infant born small for gestational age and the wide spectrum of adult-onset diseases that originate in utero.

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“…Growth hormone stimulates GLT1 expression in mouse placenta, whereas insulin-like growth factor II (IGF-II) downregulates EAAT4. Physiological concentrations of IGF-II ensure maintenance of GLT1, GLAST and EAAC1 at normal levels [48]. Several growth factors that are neuroprotective also increase transport activity.…”

Section: Regulation Of Glutamate Transportersmentioning

confidence: 99%

The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects

Kanai

Hediger

2004

Pfl�gers Archiv European Journal of Physiology

380

282

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The solute carrier family 1 (SLC1) includes five high-affinity glutamate transporters, EAAC1, GLT-1, GLAST, EAAT4 and EAAT5 (SLC1A1, SLC1A2, SLC1A3, SLC1A6, and SLC1A7, respectively) as well as the two neutral amino acid transporters, ASCT1 and ASCT2 (SLC1A4 and ALC1A5, respectively). Although each of these transporters have similar predicted structures, they exhibit distinct functional properties which are variations of a common transport mechanism. The high-affinity glutamate transporters mediate transport of l-Glu, l-Asp and d-Asp, accompanied by the cotransport of 3 Na(+) and 1 H(+), and the countertransport of 1 K(+), whereas ASC transporters mediate Na(+)-dependent exchange of small neutral amino acids such as Ala, Ser, Cys and Thr. The unique coupling of the glutamate transporters allows uphill transport of glutamate into cells against a concentration gradient. This feature plays a crucial role in protecting neurons against glutamate excitotoxicity in the central nervous system. During pathological conditions, such as brain ischemia (e.g. after a stroke), however, glutamate exit can occur due to "reversed glutamate transport", which is caused by a reversal of the electrochemical gradients of the coupling ions. Selective inhibition of the neuronal glutamate transporter EAAC1 (SLC1A1) may be of therapeutic interest to block glutamate release from neurons during ischemia. On the other hand, upregulation of the glial glutamate transporter GLT1 (SLC1A2) may help protect motor neurons in patients with amyotrophic lateral sclerosis (ALS), since loss of function of GLT1 has been associated with the pathogenesis of certain forms of ALS.

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Placental Anionic and Cationic Amino Acid Transporter Expression in Growth Hormone Overexpressing and Null IGF-II or Null IGF-I Receptor Mice

Cited by 50 publications

References 48 publications

Regulation of the Glutamate Transporters by JAK2

Regulation of the Glutamate Transporters by JAK2

Imprinted Genes, Placental Development and Fetal Growth

The glutamate/neutral amino acid transporter family SLC1: molecular, physiological and pharmacological aspects

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