Rienecker KDA, Poston RG, Segales JS, Finholm IW, Sono MH, Munteanu SJ, Ghaninejad-Esfahani M, Rejepova A, Tejeda-Garibay S, Wickman K, et al. Mild membrane depolarization in neurons induces immediate early gene transcription and acutely subdues responses to successive stimulus. Journal of Biological Chemistry. 2022.
Publications
2022
2020
Rienecker K, Poston R, Saha R. Merits and Limitations of Studying Neuronal Depolarization-Dependent Processes Using Elevated External Potassium. ASN Neuro. 2020;12:DOI: 10.1177/1759091420974807.
Poston R, Murphy L, Rejepova A, Ghaninejad-Esfahani M, Segales J, Mulligan K, Saha R. Certain Ortho-Hydroxylated Brominated Ethers Are Promiscuous Kinase Inhibitors That Impair Neuronal Signaling and Neurodevelopmental Processes. Journal of Biological Chemistry. 2020.
The developing nervous system is remarkably sensitive to environmental signals, including disruptive toxins, such as polybrominated diphenyl ethers (PBDEs). PBDEs are an environmentally pervasive class of brominated flame retardants whose neurodevelopmental toxicity mechanisms remain largely unclear. Using dissociated cortical neurons from embryonic Rattus norvegicus, we found here that chronic exposure to 6-OH-BDE-47, one of the most prevalent hydroxylated PBDE metabolites, suppresses both spontaneous and evoked neuronal electrical activity. On the basis of our previous work on MAPK/ERK kinase (MEK)–extracellular signal-related kinase (ERK) biology and our observation that 6-OH-BDE-47 is structurally similar to kinase inhibitors, we hypothesized that certain hydroxylated PBDEs mediate neurotoxicity, at least in part, by impairing the MEK–ERK axis of mitogen-activated protein kinase (MAPK) signal transduction. We tested this hypothesis on three experimental platforms: 1) in silico, where modeling ligand–protein docking suggested that 6-OH-BDE-47 is a promiscuous ATP-competitive kinase inhibitor; 2) in vitro in dissociated neurons, where 6-OH-BDE-47 and another specific hydroxylated BDE metabolite similarly impaired phosphorylation of MEK/ERK1/2 and activity-induced transcription of a neuronal immediate early gene; and 3) in vivo in Drosophila melanogaster, where developmental exposures to 6-OH-BDE-47 and a MAPK inhibitor resulted in offspring displaying similarly increased frequency of mushroom–body β–lobe midline crossing, a metric of axonal guidance. Taken together, our results support that certain ortho-hydroxylated PBDE metabolites are promiscuous kinase inhibitors and can cause disruptions of critical neurodevelopmental processes, including neuronal electrical activity, pre-synaptic functions, MEK–ERK signaling, and axonal guidance.
2019
Poston RG, Saha RN. Epigenetic Effects of Polybrominated Diphenyl Ethers on Human Health. Int J Environ Res Public Health. 2019;16(15).
Scheidegger A, Dunn CJ, Samarakkody A, Koney NK-K, Perley D, Saha RN, Nechaev S. Genome-wide RNA Pol II Initiation and Pausing in Neural Progenitors of the Rat. BMC Genomics. 2019;20:477.
2018
Poston R, Dunn C, Sarkar P, Saha R. Persistent 6-OH-BDE-47 exposure impairs functional neuronal maturation and alters expression of neurodevelopmentally-relevant chromatin remodelers. Environmental Epigenetics. 2018;4:10.1093/eep/dvx020.
Tyssowski K, NR D, JH C, CJ D, RG P, , RN S, SM D, JM G. Different Neuronal Activity Patterns Induce Different Gene Expression Programs. Neuron. 2018;98:530–546.
2017
Dunn CJ, Sarkar P, Bailey ER, Farris S, Zhao M, Ward JM, Dudek SM, Saha RN. Histone Hypervariants H2A.Z.1 and H2A.Z.2 Play Independent and Context-Specific Roles in Neuronal Activity-Induced Transcription of Arc/Arg3.1 and Other Immediate Early Genes. eNeuro. 2017;4:0040–17.
2013
Saha R, Dudek S. Splitting hares and tortoises: a classification of neuronal immediate early gene transcription based on poised RNA polymerase II. Neuroscience. 2013;247:175–181.
2011
Saha R, Wissink E, Bailey E, Zhao M, Fargo D, Hwang J, Daigle K, Fenn J, Adelman K, Dudek S. Rapid activity-induced transcription of Arc and other IEGs relies on poised RNA polymerase II. Nat Neurosci. 2011;14:848–856.