Metabotropic glutamate receptor 5 modulates nociceptive plasticity via extracellular signal-regulated kinase-Kv4.2 signaling in spinal cord dorsal horn neurons
Metabotropic glutamate receptor 5 modulates nociceptive plasticity via extracellular signal-regulated kinase-Kv4.2 signaling in spinal cord dorsal horn neurons
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DOI：
10.1523/jneurosci.0269-07.2007
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发表时间：
2007-11-28
影响因子：
5.3
通讯作者：
Gereau, Robert W.
中科院分区：
文献类型：
--
作者：
Hu, Hui-Juan;Alter, Benedict J.;Gereau, Robert W.
代谢性谷氨酸受体（mGluRs）在痛觉调节中起重要作用。I组mGluRs （mGlu1和mGlu5）通过激活细胞外信号调节激酶（ERK）信号来调节伤害感受的可塑性。我们最近报道了K+通道Kv4.2亚基是脊髓背角A型K+电流的基础，并由ERK信号通路调节。Kv4.2介导的A型电流是背角神经元兴奋性和中枢致敏性的重要决定因素，是组织损伤后超敏性的基础。在本研究中，我们证明了ERK介导的Kv4.2磷酸化是脊髓背角神经元mGlu5激活的下游。I组mGluRs的激活抑制Kv4.2介导的A型K+电流，增加背角神经元的兴奋性。这些作用是由mGlu5的激活介导的，而不是mGlu1，并且依赖于ERK的激活。对Kv4.2磷酸化位点突变体的分析清楚地确定S616是mGlu5 - ERK依赖的A型电流和兴奋性调节的残基。此外，在Kv4.2敲除小鼠中，脊髓I组mGluRs激活诱导的伤害性行为受到损害，这表明在体内，Kv4.2的调节是mGlu5激活的下游。总之，我们的研究结果表明，mGlu5的激活导致ERK介导的磷酸化和背角神经元中含有kv4.2的钾通道的调节。这种调节可能有助于与慢性炎症性疼痛相关的伤害性可塑性和中枢敏化。
Metabotropic glutamate receptors ( mGluRs) play important roles in the modulation of nociception. The group I mGluRs ( mGlu1 and mGlu5) modulate nociceptive plasticity via activation of extracellular signal- regulated kinase ( ERK) signaling. We reported recently that the K+ channel Kv4.2 subunit underlies A- type K+ currents in the spinal cord dorsal horn and is modulated by the ERK signaling pathway. Kv4.2- mediated A- type currents are important determinants of dorsal horn neuronal excitability and central sensitization that underlies hypersensitivity after tissue injury. In the present study, we demonstrate that ERK- mediated phosphorylation of Kv4.2 is downstream of mGlu5 activation in spinal cord dorsal horn neurons. Activation of group I mGluRs inhibited Kv4.2- mediated A- type K+ currents and increased neuronal excitability in dorsal horn neurons. These effects were mediated by activation of mGlu5, but not mGlu1, and were dependent on ERK activation. Analysis of Kv4.2 phosphorylation site mutants clearly identified S616 as the residue responsible for mGlu5 - ERK- dependent modulation of A- type currents and excitability. Furthermore, nociceptive behavior induced by activation of spinal group I mGluRs was impaired in Kv4.2 knock- out mice, demonstrating that, in vivo, modulation of Kv4.2 is downstream of mGlu5 activation. Altogether, our results indicate that activation of mGlu5 leads to ERK- mediated phosphorylation and modulation of Kv4.2-containing potassium channels in dorsal horn neurons. This modulation may contribute to nociceptive plasticity and central sensitization associated with chronic inflammatory pain conditions.