N-Methyl-D-Aspartate Receptor Signaling-Protein Kinases Crosstalk in Cerebral Ischemia


ENGİN A., ENGİN A. B.

PROTEIN KINASE-MEDIATED DECISIONS BETWEEN LIFE AND DEATH, vol.1275, pp.259-283, 2021 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 1275
  • Publication Date: 2021
  • Doi Number: 10.1007/978-3-030-49844-3_10
  • Journal Name: PROTEIN KINASE-MEDIATED DECISIONS BETWEEN LIFE AND DEATH
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, EMBASE, MEDLINE
  • Page Numbers: pp.259-283
  • Keywords: Stroke, N-methyl-D-aspartate (NMDA) receptor, Cerebral ischemia, Excitotoxicity, Tyrosine receptor kinase B (TrkB), Reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, Postsynaptic density-95 (PSD-95), Ephrin-B (EphB), Death-associated protein kinase 1 (DAPK1), Cyclin-dependent kinase (CDK), LYSOSOMAL MEMBRANE PERMEABILIZATION, NR2B-CONTAINING NMDA RECEPTORS, ENDOPLASMIC-RETICULUM STRESS, CYCLIN-DEPENDENT KINASES, NEURONAL CELL-DEATH, DNA-DAMAGE RESPONSE, OXIDATIVE STRESS, S-NITROSYLATION, IN-VITRO, TYROSINE PHOSPHORYLATION
  • Gazi University Affiliated: Yes

Abstract

Although stroke is very often the cause of death worldwide, the burden of ischemic and hemorrhagic stroke varies between regions and over time regarding differences in prognosis, prevalence of risk factors, and treatment strategies. Excitotoxicity, oxidative stress, dysfunction of the blood-brain barrier, neuroinflammation, and lysosomal membrane permeabilization, sequentially lead to the progressive death of neurons. In this process, protein kinases-related checkpoints tightly regulate N-methyl-D-aspartate (NMDA) receptor signaling pathways. One of the major hallmarks of cerebral ischemia is excitotoxicity, characterized by overactivation of glutamate receptors leading to intracellular Ca2+ overload and ultimately neuronal death. Thus, reduced expression of postsynaptic density-95 protein and increased protein S-nitrosylation in neurons is responsible for neuronal vulnerability in cerebral ischemia. In this chapter death-associated protein kinases, cyclin-dependent kinase 5, endoplasmic reticulum stress-induced protein kinases, hyperhomocysteinemia-related NMDA receptor overactivation, ephrin-B-dependent amplification of NMDA-evoked neuronal excitotoxicity and lysosomo-centric hypothesis have been discussed. Consequently, ample evidences have demonstrated that enhancing extrasynaptic NMDA receptor activity triggers cell death after stroke. In this context, considering the dual roles of NMDA receptors in both promoting neuronal survival and mediating neuronal damage, selective augmentation of NR2A-containing NMDA receptor activation in the presence of NR2B antagonist may constitute a promising therapy for stroke.