The Kv4.2 Potassium Channel Subunit Is Required for Pain Plasticity

Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Neuron (Impact Factor: 15.05). 05/2006; 50(1):89-100. DOI: 10.1016/j.neuron.2006.03.010
Source: PubMed


A-type potassium currents are important determinants of neuronal excitability. In spinal cord dorsal horn neurons, A-type currents are modulated by extracellular signal-regulated kinases (ERKs), which mediate central sensitization during inflammatory pain. Here, we report that Kv4.2 mediates the majority of A-type current in dorsal horn neurons and is a critical site for modulation of neuronal excitability and nociceptive behaviors. Genetic elimination of Kv4.2 reduces A-type currents and increases excitability of dorsal horn neurons, resulting in enhanced sensitivity to tactile and thermal stimuli. Furthermore, ERK-mediated modulation of excitability in dorsal horn neurons and ERK-dependent forms of pain hypersensitivity are absent in Kv4.2(-/-) mice compared to wild-type littermates. Finally, mutational analysis of Kv4.2 indicates that S616 is the functionally relevant ERK phosphorylation site for modulation of Kv4.2-mediated currents in neurons. These results show that Kv4.2 is a downstream target of ERK in spinal cord and plays a crucial role in pain plasticity.

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    • "DeLeo and Yezierski, 2001; Watkins et al., 2001a, b). On the other hand, astrocytes appear to affect spinal processing of nociceptive signaling induced by peripheral inflammation (Sweitzer et al., 1999), nerve injury (Ma and Quirion, 2002; Zhuang et al., 2006), cancer (Honore et al., 2000; Zhang et al., 2005), and spinal cord injury (Gwak et al., 2008). In this study, we revealed that i.t.-administered Ang II and III phosphorylate p38 MAPK in astrocytes as well as in neurons but not in microglial cells. "
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    ABSTRACT: We have previously demonstrated the possibility that angiotensin (Ang) II and its N-terminal metabolite Ang (1-7) act as neurotransmitters and/or neuromodulators in the spinal transmission of nociceptive information. Ang III, which is a C-terminal metabolite of Ang II, can also act on AT1 receptors but, its role in spinal nociceptive transmission remains unclear. Therefore, we examined the role of Ang III on the spinal nociceptive system in comparison with that of Ang II. Intrathecal (i.t.) administration of Ang III into mice produced a nociceptive behavior, which was dose-dependently inhibited by the co-administration of the AT1 receptor antagonist losartan and the p38 MAPK inhibitor SB203580, but not by the AT2 receptor antagonist PD123319, MEK1/2 inhibitor U0126 and JNK inhibitor SP600125. In addition, Ang III increased the phosphorylation of p38 MAPK in the dorsal lumbar spinal cord, which was inhibited by losartan. These effects were similar to those of observed with Ang II. The nociceptive behavior produced by Ang II or III was also attenuated by the administration of the astrocytic inhibitor L-α-aminoadipic acid, but not by the microglial inhibitor minocycline. Double immunohistochemical staining showed that spinal AT1 receptors were expressed on neurons and astrocytes, and that i.t. administration of either Ang II or III phosphorylated p38 MAPK in both spinal astrocytes and neurons. These results indicate that Ang III produces nociceptive behavior similar to Ang II, and suggest that the phosphorylation of p38 MAPK mediated through AT1 receptors on spinal astrocytes and neurons contributes to Ang II- and III-induced nociceptive behavior. Copyright © 2015. Published by Elsevier Ltd.
    No preview · Article · Jul 2015 · Neuropharmacology
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    • "The calcium binding protein calretinin (CR) has been used to differentiate neuronal subpopulations throughout the nervous system, including the spinal cord (Ren & Ruda, 1994). When employed as a neurochemical marker in SDH interneurons (Huang et al., 2005; Torsney et al., 2006; Fan et al., 2007) CR is thought to broadly identify a population of excitatory interneurons (Albuquerque et al., 1999). Some studies, however, have shown that CR is also expressed in GABAergic inhibitory interneurons (Huang et al., 2010). "
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    ABSTRACT: Neurons in the superficial dorsal horn (SDH) of the spinal cord play an important role in nociceptive, thermal, itch, and light touch sensations. Excitatory interneurons comprise ∼65% of all SDH neurons but surprisingly few studies have investigated their role in spinal sensory processing. Here we use a transgenic mouse to study putative excitatory SDH neurons that express the calcium binding protein calretinin (CR). Our immunocytochemical, morphological and electrophysiological analysis identified two distinct populations of CR-expressing neurons we termed "typical" and "atypical". Typical CR-expressing neurons comprised ∼85% of the population and exhibited characteristic excitatory interneuron properties including delayed firing discharge, large rapid A-type potassium currents, and central, radial or vertical cell morphologies. Atypical neurons exhibited properties consistent with inhibitory interneurons, including tonic firing or initial bursting discharge, Ih currents, and islet cell morphology. Although both typical and atypical CR-expressing neurons responded to noxious peripheral stimulation, the excitatory drive onto typical CR-expressing neurons was much stronger. Furthermore, atypical CR-expressing cells comprise at least two functionally distinct subpopulations based on their responsiveness to noxious peripheral stimulation and neurochemical profile. Together our data suggest CR-expression is not restricted to excitatory neurons in the SDH. Under normal conditions, the contribution of "typical" excitatory CR-expressing neurons to overall SDH excitability may be limited by the presence of A-type potassium currents, which limit the effectiveness of their strong excitatory input. Their contribution may, however, be increased in pathological situations where A-type potassium currents are decreased. By contrast, "atypical" inhibitory neurons with their excitable phenotype but weak excitatory input may be more easily recruited during increased peripheral stimulation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jul 2015 · The Journal of Physiology
    • "Further, the same group found a naturally occurring peptide (Hge36) in the venom in which the first 25 N-terminal amino acids are identical to HgeScplp1 (from 29 to 53). Similar to C-HgeScplpDig, the cytolytic action of Hge36 is quite poor, but it is a Kv1.1 blocker [18]. We did not perform other cytolytic tests with Ts19 Frag-II (e.g. "
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    ABSTRACT: Ts19 Fragment II (Ts19 Frag-II) was first isolated from the venom of the scorpion Tityus serrulatus (Ts). It is a protein presenting 49 amino acid residues, three disulfide bridges, Mr 5,534Da and was classified as a new member of class (subfamily) 2 of the β-KTxs, the second one described for Ts scorpion. The β-KTx family is composed by two-domain peptides: N-terminal helical domain (NHD), with cytolytic activity, and a C-terminal CSαβ domain (CCD), with Kv blocking activity. The extensive electrophysiological screening (16 Kv channels and 5 Nav channels) showed that Ts19 Frag-II presents a specific and significant blocking effect on Kv1.2 (IC50 value of 544±32nM). However, no cytolytic activity was observed with this toxin. We conclude that the absence of 9 amino acid residues from the N-terminal sequence (compared to Ts19 Frag-I) is responsible for the absence of cytolytic activity. In order to prove this hypothesis, we synthesized the peptide with these 9 amino acid residues, called Ts19 Frag-III. As expected, Ts19 Frag-III showed to be cytolytic and did not block the Kv1.2 channel. The post-translational modifications of Ts19 and its fragments (I-III) are also discussed here. A mechanism of post-translational processing (post-splitting) is suggested to explain Ts19 fragments production. In addition to the discovery of this new toxin, this report provides further evidence for the existence of several compounds in the scorpion venom contributing to the diversity of the venom arsenal. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jun 2015 · Peptides
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