K⁺ channel Kv4.1 is expressed in the nociceptors/secondary nociceptive neurons and participates in pain regulation

Abstract

Background Kv4 channels are key components controlling neuronal excitability at membrane potentials below action potential thresholds. It remains elusive whether Kv4.1 participates in pain regulation. Methods We raised a Kv4.1 antibody to map Kv4.1+ neurons in the superficial dorsal horn of the spinal cord and dorsal root ganglion (DRG) of rats. Behavioural, biochemical and immunohistochemical methods were used to examine whether the activity of Kv4.1+ neurons or Kv4.1 expression level is altered after peripheral nerve injury. Results In lamina I of the spinal cord, Kv4.1 immunoreactivity (IR) was detected in neurokinin‐1 receptor positive (NK1R)+ projection neurons (the secondary nociceptive neurons) and NK1R+ excitatory interneurons. Kv4.1, KChIP2 and DPP10 were co‐expressed in these neurons. Peripheral nerve injury evoked by lumbar spinal nerve ligation (SNL) immediately induced phosphorylated extracellular regulated protein kinase (pERK, an indicator of enhanced neuronal activity) in lamina I Kv4.1+ neurons and lamina II Kv4.2/Kv4.3+ neurons of the spinal cord. Furthermore, Kv4.1 appeared in 59.9% of DRG neurons with variable sizes. Kv4.1 mRNA and protein levels in DRG neurons were gradually decreased after SNL. Following intrathecal injection of Kv4.1 antisense oligodeoxynucleotide (ASO) into naive rats, Kv4.1 protein level was reduced in the DRG, and mechanical but not thermal hypersensitivity was induced. Conclusions Kv4.1 appears in the secondary nociceptive neurons, and peripheral nerve injury increases the activity of these neurons. Kv4.1 expression in DRG neurons (including half of the nociceptors) is gradually reduced after peripheral nerve injury, and knockdown of Kv4.1 in DRG neurons induces pain. Thus, Kv4.1 participates in pain regulation. Significance Based on the expression of Kv4.1 and Kv4.3 in the nociceptors, Kv4.1 in the secondary nociceptive neurons, Kv4.1 in spinal lamina I excitatory interneurons that regulate the activity of the secondary nociceptive neurons, as well as Kv4.2 and Kv4.3 in spinal lamina II excitatory interneurons that also regulate the activity of the secondary nociceptive neurons, developing Kv4 activators or genetic manipulation to increase Kv4 channel activity in these pain‐related Kv4+ neurons will be useful in future pain therapeutics.

Etiological involvement of KCND1 variants in an X-linked neurodevelopmental disorder with variable expressivity

“…It is obvious that the amount and distribution of A-type channels on the cell surface as well as their biophysical properties, especially their macroscopic inactivation kinetics, are critical for this function. However, none of the reported Kv4.1-associated functional roles, including hippocampal pattern separation, 52 clock gene expression, 51 control of striatal circuitry, 53 or nociception, 50 appear to directly relate to the neurodevelopmental disease phenotype described herein. Intriguingly, Kv4.1 has also been implicated in the control of cell proliferation, not only in tumor cells, 55 , 56 but also in neural stem and progenitor cells.…”

“…While KCND1 expression seems to be relatively moderate compared to other ion channel genes, 34 , 49 it is widely expressed throughout the human brain and has been shown to be involved in the control of slow repetitive action potential firing in many different neurons. 50 , 51 , 52 , 53 This is reminiscent of the A-type current function originally identified in primitive animals, 54 where these channels appear to already activate at very negative membrane potentials well below threshold. Thereby, they cause a delay in firing until A-type channel inactivation allows for the next spike.…”