Glucocorticoids modulate neural activity via a rapid non-genomic effect on Kv2.2 channels in the central nervous system

Yuqi Wang; Yuchen Zhang; Jiawei Hu; Chengfang Pan; Yiming Gao; Qingzhuo Liu; Wendong Xu; Lei Xue; Changlong Hu

Neurobiology of Stress (Jan 2024)

Glucocorticoids modulate neural activity via a rapid non-genomic effect on Kv2.2 channels in the central nervous system

Yuqi Wang,
Yuchen Zhang,
Jiawei Hu,
Chengfang Pan,
Yiming Gao,
Qingzhuo Liu,
Wendong Xu,
Lei Xue,
Changlong Hu

Affiliations

Yuqi Wang: State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, PR China; Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, 200438, PR China
Yuchen Zhang: State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, PR China; Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, 200438, PR China
Jiawei Hu: State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, PR China; Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, 200438, PR China
Chengfang Pan: State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, PR China; Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, 200438, PR China
Yiming Gao: State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, PR China; Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, 200438, PR China
Qingzhuo Liu: State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, PR China; Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, 200438, PR China
Wendong Xu: State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, PR China; The National Clinical Research Center for Aging and Medicine, Center for the Reconstruction of Limb Function, Hand Surgery Department, Huashan Hospital, Fudan University, Shanghai, 200040, PR China
Lei Xue: State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, PR China; Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, 200438, PR China; Research Institute of Intelligent Complex Systems, Fudan University, Shanghai, 200433, PR China; Corresponding author. State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, PR China.
Changlong Hu: State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, PR China; Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, 200438, PR China; International Human Phenome Institute (Shanghai), Shanghai, 200433, PR China; Corresponding author. Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, 200438, PR China.

Journal volume & issue: Vol. 28
p. 100593

Abstract

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Glucocorticoids are primary stress hormones that exert neuronal effects via both genomic and non-genomic signaling pathways. However, their rapid non-genomic effects and underlying mechanisms on neural activities remain elusive. In the present study, we investigated the rapid non-genomic effect of glucocorticoids on Kv2.2 channels in cultured HEK293 cells and acute brain slices including cortical pyramidal neurons and calyx-type synapses in the brain stem. We found that cortisol, the endogenous glucocorticoids, rapidly increased Kv2.2 currents by increasing the single-channel open probability in Kv2.2-expressing HEK293 cells through activation of the membrane-associated glucocorticoid receptor. Bovine serum albumin-conjugated dexamethasone, a membrane-impermeable agonist of the glucocorticoid receptor, could mimic the effect of cortisol on Kv2.2 channels. The cortisol-increased Kv2.2 currents were induced by activation of the extracellular signal-regulated protein kinase (ERK) 1/2 kinase, which could be inhibited by U0126, an antagonist of the ERK signaling pathway. In layer 2 cortical pyramidal neurons and the calyx of Held synapses, cortisol suppressed the action potential firing frequency during depolarization and reduced the successful rate upon high-frequency stimulation by activating Kv2.2 channels. We further examined the postsynaptic responses and found that cortisol did not affect the mEPSC and evoked EPSC, but increased the activity-dependent synaptic depression induced by a high-frequency stimulus train. In conclusion, glucocorticoids can rapidly activate Kv2.2 channels through membrane-associated glucocorticoid receptors via the ERK1/2 signaling pathway, suppress presynaptic action potential firing, and inhibit synaptic transmission and plasticity. This may be a universal mechanism of the glucocorticoid-induced non-genomic effects in the central nervous system.

Published in Neurobiology of Stress

ISSN: 2352-2895 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry: Neurology. Diseases of the nervous system; Science: Physiology: Neurophysiology and neuropsychology
Website: http://www.journals.elsevier.com/neurobiology-of-stress/

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