title: Kv2 dysfunction after peripheral axotomy enhances sensory neuron responsiveness to sustained input.
abstract: Peripheral nerve injuries caused by trauma are associated with increased sensory neuron excitability and debilitating chronic pain symptoms. Axotomy-induced alterations in the function of ion channels are thought to largely underlie the pathophysiology of these phenotypes. Here, we characterise the mRNA distribution of Kv2 family members in rat dorsal root ganglia (DRG) and describe a link between Kv2 function and modulation of sensory neuron excitability. Kv2.1 and Kv2.2 were amply expressed in cells of all sizes, being particularly abundant in medium-large neurons also immunoreactive for neurofilament-200. Peripheral axotomy led to a rapid, robust and long-lasting transcriptional Kv2 downregulation in the DRG, correlated with the onset of mechanical and thermal hypersensitivity. The consequences of Kv2 loss-of-function were subsequently investigated in myelinated neurons using intracellular recordings on ex vivo DRG preparations. In naïve neurons, pharmacological Kv2.1/Kv2.2 inhibition by stromatoxin-1 (ScTx) resulted in shortening of action potential (AP) after-hyperpolarization (AHP). In contrast, ScTx application on axotomized neurons did not alter AHP duration, consistent with the injury-induced Kv2 downregulation. In accordance with a shortened AHP, ScTx treatment also reduced the refractory period and improved AP conduction to the cell soma during high frequency stimulation. These results suggest that Kv2 downregulation following traumatic nerve lesion facilitates greater fidelity of repetitive firing during prolonged input and thus normal Kv2 function is postulated to limit neuronal excitability. In summary, we have profiled Kv2 expression in sensory neurons and provide evidence for the contribution of Kv2 dysfunction in the generation of hyperexcitable phenotypes encountered in chronic pain states.
authors.affiliation: Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK. Electronic address: c.tsantoulas@gmail.com.
authors.forename: Christoforos
authors.initials: C
authors.lastname: Tsantoulas
authors.affiliation: Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK. Electronic address: lan.zhu@kcl.ac.uk.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Centre for Neuroscience & Trauma, Blizard Institute, Bart's and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Ping
authors.initials: P
authors.lastname: Yip
authors.affiliation: Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.
authors.forename: John
authors.initials: J
authors.lastname: Grist
authors.affiliation: Centre for Neuroscience & Trauma, Blizard Institute, Bart's and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Michael
authors.affiliation: Neurorestoration Group, Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: McMahon
mesh_terms: D000818:Animals; D019771:Axotomy / Q000379:methods; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010146:Pain / Q000209:etiology / Q000378:metabolism; D010147:Pain Measurement; D010523:Peripheral Nervous System Diseases / Q000150:complications / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000378:metabolism* / Q000502:physiology; D051669:Shab Potassium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D051669:Shab Potassium Channels; D015740:Calcitonin Gene-Related Peptide
keywords: AHPD50; AP; AP half width; APD50; ATF3; CGRP; CNS; DRG; Dorsal root ganglia; GAPDH; IB4; IHC; IR; ISH; Kv channel; NF200; Neuropathic pain; Potassium channel; RP; SNT; ScTx; action potential; activating transcription factor 3; after-hyperpolarization half width; calcitonin gene-related peptide; central nervous system; dorsal root ganglion; glyceraldehyde 3-phosphate dehydrogenase; immunohistochemistry; in situ hybridization; input resistance; isolectin B4; neurofilament 200; refractory period; spinal nerve transection; stromatoxin-1; voltage-gated potassium channel