Nihar R. Pandey

Publications (29) View all

• Article: Cell-type-specific roles of IGF-1R and EGFR in mediating Zn2+-induced ERK1/2 and PKB phosphorylation

  Nihar R. Pandey, George Vardatsikos, Mohamad Z. Mehdi, Ashok K. Srivastava
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  ABSTRACT: Zn2+ exerts insulin-mimetic and antidiabetic effects in rodent models of insulin resistance, and activates extracellular-signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase B (PKB), key components of the insulin signaling pathway. Zn2+-induced signaling has been shown to be associated with an increase in the tyrosine phosphorylation of insulin receptor (IR), as well as of insulin-like growth factor1 receptor (IGF-1R) and epidermal growth factor receptor (EGFR) in several cell types. However, the specific contribution of these receptor protein tyrosine kinases (R-PTKs) in mediating Zn2+-induced responses in a cell-specific fashion remains to be established. Therefore, using a series of pharmacological inhibitors and genetically engineered cells, we have investigated the roles of various R-PTKs in Zn2+-induced ERK1/2 and PKB phosphorylation. Pretreatment of Chinese hamster ovary (CHO) cells overexpressing a human IR (CHO-HIR cells) with AG1024, an inhibitor for IR protein tyrosine kinase (PTK) and IGF-1R-PTK, blocked Zn2+-induced ERK1/2 and PKB phosphorylation, but AG1478, an inhibitor for EGFR, was without effect in CHO cells. On the other hand, both of these inhibitors were able to attenuate Zn2+-induced phosphorylation of ERK1/2 and PKB in A10 vascular smooth muscle cells. In addition, in CHO cells overexpressing tyrosine kinase deficient IR, Zn2+ was still able to induce the phosphorylation of these two signaling molecules, whereas the insulin effect was significantly attenuated. Furthermore, both Zn2+ and insulin-like growth factor1 failed to stimulate ERK1/2 and PKB phosphorylation in IGF-1R knockout cells. Also, Zn2+-induced responses in CHO-HIR cells were not associated with an increase in the tyrosine phosphorylation of the IR β-subunit and insulin receptor substrate1 in CHO-HIR cells. Taken together, these data suggest that distinct R-PTKs mediate Zn2+-evoked ERK1/2 and PKB phosphorylation in a cell-specific manner. KeywordsInsulin signaling-Zinc-Extracellular-signal-regulated kinases 1 and 2-Protein kinase B-Protein tyrosine kinases-IGF-1R-EGFR
  JBIC Journal of Biological Inorganic Chemistry 05/2012; 15(3):399-407. · 3.29 Impact Factor
• Article: LIM Domain Only 4 (LMO4) Regulates Calcium-Induced Calcium Release and Synaptic Plasticity in the Hippocampus.

  Zhaohong Qin, Xun Zhou, Mariana Gomez-Smith, Nihar R. Pandey, Kevin F. H. Lee, Diane C. Lagace, Jean-Claude Béïque, Hsiao-Huei Chen
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  ABSTRACT: The LIM domain only 4 (LMO4) transcription cofactor activates gene expression in neurons and regulates key aspects of network formation, but the mechanisms are poorly understood. Here, we show that LMO4 positively regulates ryanodine receptor type 2 (RyR2) expression, thereby suggesting that LMO4 regulates calcium-induced calcium release (CICR) in central neurons. We found that CICR modulation of the afterhyperpolarization in CA3 neurons from mice carrying a forebrain-specific deletion of LMO4 (LMO4 KO) was severely compromised but could be restored by single-cell overexpression of LMO4. In line with these findings, two-photon calcium imaging experiments showed that the potentiation of RyR-mediated calcium release from internal stores by caffeine was absent in LMO4 KO neurons. The overall facilitatory effect of CICR on glutamate release induced during trains of action potentials was likewise defective in LMO4 KO, confirming that CICR machinery is severely compromised in these neurons. Moreover, the magnitude of CA3-CA1 long-term potentiation was reduced in LMO4 KO mice, a defect that appears to be secondary to an overall reduced glutamate release probability. These cellular phenotypes in LMO4 KO mice were accompanied with deficits in hippocampus-dependent spatial learning as determined by the Morris water maze test. Thus, our results establish LMO4 as a key regulator of CICR in central neurons, providing a mechanism for LMO4 to modulate a wide range of neuronal functions and behavior.
  Journal of Neuroscience 03/2012; 32(12-J Neurosci. 2012 Mar 21;32(12):4271-4283.):4271-4283. · 7.11 Impact Factor
• Article: Cardiovascular effects of tight versus usual blood-pressure control.

  Saurabh Rai, Nidhi Nandan, Rashmi Tiwari-Pandey, Nihar R Pandey
  The Lancet 11/2009; 374(9703):1741; author reply 1742. · 38.28 Impact Factor
• Article: CaMKII knockdown attenuates H2O2-induced phosphorylation of ERK1/2, PKB/Akt, and IGF-1R in vascular smooth muscle cells.

  Ali Bouallegue, Nihar R Pandey, Ashok K Srivastava
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  ABSTRACT: We have shown earlier a requirement for Ca(2+) and calmodulin (CaM) in the H(2)O(2)-induced activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase B (PKB), key mediators of growth-promoting, proliferative, and hypertrophic responses in vascular smooth muscle cells (VSMC). Because the effect of CaM is mediated through CaM-dependent protein kinase II (CaMKII), we have investigated here the potential role of CaMKII in H(2)O(2)-induced ERK1/2 and PKB phosphorylation by using pharmacological inhibitors of CaM and CaMKII, a CaMKII inhibitor peptide, and siRNA knockdown strategies for CaMKII alpha. Calmidazolium and W-7, antagonists of CaM, as well as KN-93, a specific inhibitor of CaMKII, attenuated H(2)O(2)-induced responses of ERK1/2 and PKB phosphorylation in a dose-dependent fashion. Similar to H(2)O(2), calmidazolium and KN-93 also exhibited an inhibitory effect on glucose/glucose oxidase-induced phosphorylation of ERK1/2 and PKB in these cells. Transfection of VSMC with CaMKII autoinhibitory peptide corresponding to the autoinhibitory domain (aa 281-309) of CaMKII and with siRNA of CaMKII alpha attenuated the H(2)O(2)-induced phosphorylation of ERK1/2 and PKB. In addition, calmidazolium and KN-93 blocked H(2)O(2)-induced Pyk2 and insulin-like growth factor-1 receptor (IGF-1R) phosphorylation. Moreover, treatment of VSMC with CaMKII alpha siRNA abolished the H(2)O(2)-induced IGF-1R phosphorylation. H(2)O(2) treatment also induced Thr(286) phosphorylation of CaMKII, which was inhibited by both calmidazolium and KN-93. These results demonstrate that CaMKII plays a critical upstream role in mediating the effects of H(2)O(2) on ERK1/2, PKB, and IGF-1R phosphorylation.
  Free radical biology & medicine 07/2009; 47(6):858-66. · 5.42 Impact Factor
• Article: Hepatic high-density lipoprotein secretion regulates the mobilization of cell-surface hepatic lipase.

  Cynthia Chatterjee, Elizabeth K Young, Kusala A Pussegoda, Erin E Twomey, Nihar R Pandey, Daniel L Sparks
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  ABSTRACT: HDL acts much like heparin to liberate hepatic lipase (HL) from cell surface proteoglycans and stimulate triglyceride clearance. Experiments were undertaken to evaluate the effects of factors that stimulate the secretion of HDL from the liver on the release of HL. Treatment of HepG2 cells with linoleic acid phospholipids (LAPL) (12 muM) promotes a similar increase in the accumulation of both HDL and HL in the cell media. LAPL also induce both apoA-I and HL release from primary human hepatocytes. Dilinoleoylphosphatidylcholine has a greater effect on both apoA-I secretion and HL release than palmitoyllinoleoylphosphatidylcholine. HL released from HepG2 cells is inactive and associated with a large HDL complex containing both apoA-I and apoA-II. Inclusion of the PPARalpha inhibitor, MK-886, or MAPK inhibitor, U0126, completely blocks the LAPL-induced apoA-I and HL accumulation in the media. LAPL-treated cell lysates, however, showed no change in HL protein expression nor HL mRNA. LAPL-induced HL release appears to be a consequence of the displacement ability of newly secreted HDL. Overexpression of pre-pro-apoA-I in HepG2 cells increased HL release, while siRNA inhibition of the apoA-I gene reduced HL in the media. The data show that factors that stimulate HDL secretion in hepatocytes act to also increase the release of HL. This may partly explain why HDL therapeutics often impact plasma triglyceride levels.
  Biochemistry 06/2009; 48(25):5994-6001. · 3.42 Impact Factor