The entire γ‐carboxyglutamic acid‐ and helical stack‐domains of human coagulation factor IX are required for optimal binding to its endothelial cell receptor

Prorok, Mary; Geng, Jieping; Warder, Scott E.

doi:10.1111/j.1399-3011.1996.tb00842.x

Cited by 7 publications

(6 citation statements)

References 20 publications

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“…The methods used for the syntheses have been published earlier (Prorok et al, 1996). A C-terminal truncated analogue of con-R was used (con-R[1-17]), which has been previously shown to contain essentially all of the NMDAR activity of the 27 residue native peptide (Blandl et al, 2001).…”

Section: Experimental Methodsmentioning

confidence: 99%

Conantokins inhibit NMDAR-dependent calcium influx in developing rat hippocampal neurons in primary culture with resulting effects on CREB phosphorylation

Huang¹,

Balsara²,

Sheng³

et al. 2010

Molecular and Cellular Neuroscience

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The effects of conantokin (con)-G, con-R [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17], and con-T on ion flow through N-methyl-Daspartate receptor (NMDAR) ion channels were determined in cultured primary rat hippocampal neurons. The potency of con-G diminished, whereas inhibition by con-R[1-17] and con-T did not change, as the neurons matured. Con-G, con-R[1-17], and con-T effectively diminished NMDAinduced Ca 2+ influx into the cells. A similar age-dependent decrease in con-G-mediated inhibition of the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) was observed, compared to con-R[1-17] and con-T. The effects of the conantokins on NMDA-induced cAMP response element-binding protein (CREB) phosphorylation in immature (DIV 9) and mature (DIV 16) neurons showed that, at DIV 9, con-G, con-R[1-17], and con-T inhibited NMDA-mediated P-CREB levels, whereas in DIV 16 neurons the conantokins did not inhibit overall levels of NMDAinduced P-CREB. In contrast, P-CREB levels were enhanced through inhibition of the protein phosphatases, PP1 and PP2B (calcineurin). This ability of conantokins to sustain CREB phosphorylation can thus enhance neuronal survival and plasticity.

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Section: Experimental Methodsmentioning

confidence: 99%

Conantokins inhibit NMDAR-dependent calcium influx in developing rat hippocampal neurons in primary culture with resulting effects on CREB phosphorylation

Huang¹,

Balsara²,

Sheng³

et al. 2010

Molecular and Cellular Neuroscience

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“…The following conantokins were chemically synthesized as described earlier [ 8 ], where γ refers to γ-carboxyglutamate:…”

Section: Methodsmentioning

confidence: 99%

“…ConT assumes a high degree of α-helicity in the metal-free (apo) state, whereas ConG adopts a random conformation in absence of divalent ions [ 6 , 7 ]. However, ConG binds to divalent cations to generate an α-helical structure comparable to apo- or metal-bound ConT [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Antagonist Properties of Conus parius Peptides on N-Methyl-D-Aspartate Receptors and Their Effects on CREB Signaling

et al. 2013

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Three members of a family of small neurotoxic peptides from the venom of Conus parius, conantokins (Con) Pr1, Pr2, and Pr3, function as antagonists of N-methyl-D-aspartate receptors (NMDAR). We report structural characterizations of these synthetic peptides, and also demonstrate their antagonistic properties toward ion flow through NMDAR ion channels in primary neurons. ConPr1 and ConPr2 displayed moderate increases in α-helicity after addition of Mg2+. Native apo-ConPr3 possessed an α-helical conformation, and the helicity increased only slightly on addition of Mg2+. Additionally, these peptides diminished NMDA/Gly-mediated currents and intracellular Ca2+ (iCa2+) influx in mature rat primary hippocampal neurons. Electrophysiological data showed that these peptides displayed slower antagonistic properties toward the NMDAR than conantokins from other species of cone snails, e.g., ConT and ConG. Furthermore, to demonstrate selectivity of the C. parius-derived conantokins towards specific NMDAR subunits, cortical neurons from GluN2A-/- and GluN2B-/- mice were utilized. Robust inhibition of NMDAR-mediated stimulation in GluN2A-/--derived mouse neurons, as compared to those isolated from GluN2B-/--mouse brains, was observed, suggesting a greater selectivity of these antagonists towards the GluN2B subunit. These C. parius conantokins mildly inhibited NMDAR-induced phosphorylation of CREB at Ser133, suggesting that the peptides modulated iCa2+ entry and, thereby, activation of CREB, a transcription factor that is required for maintaining long-term synaptic activity. Our data mechanistically show that while these peptides effectively antagonize NMDAR-directed current and iCa2+ influx, receptor-coupled CREB signaling is maintained. The consequence of sustained CREB signaling is improved neuronal plasticity and survival during neuropathologies.

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“…Vitamin K-dependent coagulation factors include II, VII, IX, and X. Vitamin K deficiency or utilization disorders may affect the γ-carboxylation of glutamate, and thus, the γ-carboxyglutamyl glutamic acid residue in these coagulation factors could not form [1, 2]. Vitamin K-dependent coagulopathy is characterized by decreased activity of coagulation factors and coagulation dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Fatal Vitamin K-Dependent Coagulopathy Associated with Cefoperazone/Sulbactam: A Case Report

2019

Drug Saf - Case Rep

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This case report describes a suspected and fatal adverse reaction involving vitamin K-dependent coagulopathy that might be associated with cefoperazone/sulbactam (CPZ/SAM), a combined antimicrobial formulation. We reported a patient diagnosed with acute cerebral infarction and secondary pulmonary infection who was treated with an intravenous infusion of CPZ/SAM at 3 g twice daily. After receiving treatment with CPZ/SAM, the patient developed a fatal adverse reaction of CPZ-induced hemorrhage. The Naranjo assessment score in this report was 5, suggesting that the patient’s coagulation function disorder was potentially associated with the use of CPZ/SAM. To prevent vitamin K-dependent coagulopathy caused by CPZ/SAM, it is suggested to avoid cephalosporins in patients with a high risk of bleeding unless the need for cephalosporins is compelling.

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The entire γ‐carboxyglutamic acid‐ and helical stack‐domains of human coagulation factor IX are required for optimal binding to its endothelial cell receptor

Cited by 7 publications

References 20 publications

Conantokins inhibit NMDAR-dependent calcium influx in developing rat hippocampal neurons in primary culture with resulting effects on CREB phosphorylation

Conantokins inhibit NMDAR-dependent calcium influx in developing rat hippocampal neurons in primary culture with resulting effects on CREB phosphorylation

Antagonist Properties of Conus parius Peptides on N-Methyl-D-Aspartate Receptors and Their Effects on CREB Signaling

Fatal Vitamin K-Dependent Coagulopathy Associated with Cefoperazone/Sulbactam: A Case Report

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