Balanced Activity between Kv3 and Nav Channels Determines Fast-Spiking in Mammalian Central Neurons

Yuanzheng Gu; Dustin Servello; Zhi Han; Rupa R Lalchandani; Jun B Ding; Kun Huang; Chen Gu

doi:10.1016/j.isci.2018.10.014

Balanced Activity between Kv3 and Nav Channels Determines Fast-Spiking in Mammalian Central Neurons

iScience. 2018 Nov 30:9:120-137. doi: 10.1016/j.isci.2018.10.014. Epub 2018 Oct 18.

Authors

Yuanzheng Gu¹, Dustin Servello², Zhi Han³, Rupa R Lalchandani⁴, Jun B Ding⁴, Kun Huang⁵, Chen Gu⁶

Affiliations

¹ Department of Biological Chemistry and Pharmacology, The Ohio State University, 182 Rightmire Hall, 1060 Carmack Road, Columbus, OH 43210, USA.
² Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH 43210, USA.
³ Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; College of Software, Nankai University, Tianjin 300071, China; Regenstrief Institute, Indianapolis, IN 46202, USA.
⁴ Department of Neurosurgery, and Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, CA, USA.
⁵ Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Regenstrief Institute, Indianapolis, IN 46202, USA; School of Biomedical Engineering, Shenzhen University, Shenzhen 518037, China.
⁶ Department of Biological Chemistry and Pharmacology, The Ohio State University, 182 Rightmire Hall, 1060 Carmack Road, Columbus, OH 43210, USA; Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, OH 43210, USA. Electronic address: gu.49@osu.edu.

Abstract

Fast-spiking (FS) neurons can fire action potentials (APs) up to 1,000 Hz and play key roles in vital functions such as sound location, motor coordination, and cognition. Here we report that the concerted actions of Kv3 voltage-gated K⁺ (Kv) and Na⁺ (Nav) channels are sufficient and necessary for inducing and maintaining FS. Voltage-clamp analysis revealed a robust correlation between the Kv3/Nav current ratio and FS. Expressing Kv3 channels alone could convert ∼30%-60% slow-spiking (SS) neurons to FS in culture. In contrast, co-expression of either Nav1.2 or Nav1.6 together with Kv3.1 or Kv3.3, but not alone or with Kv1.2, converted SS to FS with 100% efficiency. Furthermore, RNA-sequencing-based genome-wide analysis revealed that the Kv3/Nav ratio and Kv3 expression levels strongly correlated with the maximal AP frequencies. Therefore, FS is established by the properly balanced activities of Kv3 and Nav channels and could be further fine-tuned by channel biophysical features and localization patterns.

Keywords: Biophysics; Molecular Neuroscience; Neuroscience.

Abstract

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