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

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

  • Neurobiol Stress. 2023 Nov 25:28:100593. doi: 10.1016/j.ynstr.2023.100593.
Yuqi Wang 1 2,  Yuchen Zhang 1 2,  Jiawei Hu 1 2,  Chengfang Pan 1 2,  Yiming Gao 1 2,  Qingzhuo Liu 1 2,  Wendong Xu 1 3,  Lei Xue 1 2 4,  Changlong Hu 1 2 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200433, PR China.
  • 2 Department of Physiology and Neurobiology, School of Life Sciences, Fudan University, Shanghai, 200438, PR China.
  • 3 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.
  • 4 Research Institute of Intelligent Complex Systems, Fudan University, Shanghai, 200433, PR China.
  • 5 International Human Phenome Institute (Shanghai), Shanghai, 200433, PR China.
PMID: 38075025 DOI: 10.1016/j.ynstr.2023.100593
Abstract

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.

Keywords

Glucocorticoid; Kv2.2 channel; Neural activity; Non-genomic effect.

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