ABSTRACT
Calcium signaling is integral for neuronal activity and synaptic plasticity. We demonstrate that the calcium response generated by different sources modulates neuronal activity-mediated protein synthesis, another process essential for synaptic plasticity. Stimulation of NMDARs generates a protein synthesis response involving three phases-increased translation inhibition, followed by a decrease in translation inhibition, and increased translation activation. We show that these phases are linked to NMDAR-mediated calcium response. Calcium influx through NMDARs elicits increased translation inhibition, which is necessary for the successive phases. Calcium through L-VGCCs acts as a switch from translation inhibition to the activation phase. NMDAR-mediated translation activation requires the contribution of L-VGCCs, RyRs, and SOCE. Furthermore, we show that IP3-mediated calcium release and SOCE are essential for mGluR-mediated translation up-regulation. Finally, we signify the relevance of our findings in the context of Alzheimer's disease. Using neurons derived from human fAD iPSCs and transgenic AD mice, we demonstrate the dysregulation of NMDAR-mediated calcium and translation response. Our study highlights the complex interplay between calcium signaling and protein synthesis, and its implications in neurodegeneration.
Subject(s)
Calcium Signaling , Calcium , Neurons , Protein Biosynthesis , Receptors, Metabotropic Glutamate , Receptors, N-Methyl-D-Aspartate , Animals , Receptors, N-Methyl-D-Aspartate/metabolism , Mice , Calcium/metabolism , Receptors, Metabotropic Glutamate/metabolism , Humans , Neurons/metabolism , Mice, Transgenic , Alzheimer Disease/metabolism , Neuronal Plasticity , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/cytologyABSTRACT
The wide disparity in coronavirus disease (COVID-19)-related death rates based upon the ethnic origin is well established by now. The higher incidence of COVID-19 deaths amongst the healthcare staff belonging to black and minority ethnic (BAME) communities living in the United Kingdom has generated a great deal of concern and anxiety in clinicians. Public Health England (PHE) has outlined mitigation strategies after immense pressure from professional organisations and influential clinical leaders. Although seemingly well thought through, these measures fall short of addressing the professional, moral and emotional dilemma faced by the BAME clinicians who feel that they are being expected to choose between their duty towards their patients and the profession, and their responsibility to look after their own health.
