Molecular identity of axonal sodium channels in human cortical pyramidal cells

Abstract

Studies in rodents revealed that selective accumulation of Na+ channel subtypes at the axon initial segment (AIS) determines action potential (AP) initiation and backpropagation in cortical pyramidal cells (PCs); however, in human cortex, the molecular identity of Na+ channels distributed at PC axons, including the AIS and the nodes of Ranvier, remains unclear. We performed immunostaining experiments in human cortical tissues removed surgically to cure brain diseases. We found strong immunosignals of Na+ channels and two channel subtypes, NaV1.2 and NaV1.6, at the AIS of human cortical PCs. Although both channel subtypes were expressed along the entire AIS, the peak immunosignals of NaV1.2 and NaV1.6 were found at proximal and distal AIS regions, respectively. Surprisingly, in addition to the presence of NaV1.6 at the nodes of Ranvier, NaV1.2 was also found in a subpopulation of nodes in the adult human cortex, different from the absence of NaV1.2 in myelinated axons in rodents. NaV1.1 immunosignals were not detected at either the AIS or the nodes of Ranvier of PCs; however, they were expressed at interneuron axons with different distribution patterns. Further experiments revealed that parvalbumin-positive GABAergic axon cartridges selectively innervated distal AIS regions with relatively high immunosignals of NaV1.6 but not the proximal NaV1.2-enriched compartments, suggesting an important role of axo-axonic cells in regulating AP initiation in human PCs. Together, our results show that both NaV1.2 and NaV1.6 (but not NaV1.1) channel subtypes are expressed at the AIS and the nodes of Ranvier in adult human cortical PCs, suggesting that these channel subtypes control neuronal excitability and signal conduction in PC axons.

Functional implications of axon initial segment cytoskeletal disruption in stroke

“…In both PV and SST interneurons, Na v 1.6 channels were found in the distal part of the AIS, whereas Na v 1.2 channels were found in the proximal part of the AIS only in SST-positive INs [60] . A recent study showed that, in human cortical pyramidal cells, the pattern of Na + channel distribution is similar to that in rodents [64] . The primary difference was a clustering of Na v 1.2 channel in some nodes of Ranvier in addition to the Na v 1.6 channels.…”

“…TRPM2 channels are thought to be activated by reactive oxygen species (ROS), nitric oxide (NO), and ADP-ribose (ADPR) [89] . TRPM7 channels can be activated through low extracellular divalent cations, ROS, and pH changes [64] . All of the above are present in neuronal injury areas.…”

The Segregated Expression of Voltage-Gated Potassium and Sodium Channels in Neuronal Membranes: Functional Implications and Regulatory Mechanisms

“…In addition, and correlating with the predominant localization of Nav1.1 in the AIS of GABAergic neurons (Ogiwara et al, 2007; Lorincz and Nusser, 2008; Catterall et al, 2010; Tian et al, 2014), the loss of proper localization and function of Nav1.1 is considered to be a factor for the onset of epilepsy caused by a disruption of the inhibitory balance in the brain (Catterall et al, 2010). …”

Opposing Effects on Na V 1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures

“…SCN2A stands out from other ASD-associated genes in several ways. First, while most ASD-associated genes are related to either chromatin regulation or synapse structure (2), Na V 1.2 channels are primarily expressed in the axon (6–10). Second, along with de novo PTVs, an excess of de novo missense mutations is also observed in SCN2A , a pattern seen in no other gene (2).…”