MrgD activation inhibits KCNQ/M-currents and contributes to enhanced neuronal excitability
MrgD activation inhibits KCNQ/M-currents and contributes to enhanced neuronal excitability
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DOI：
10.1523/jneurosci.4932-06.2007
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发表时间：
2007-04-18
影响因子：
5.3
通讯作者：
Pausch, Mark H.
中科院分区：
文献类型：
--
作者：
Crozier, Robert A.;Ajit, Seena K.;Pausch, Mark H.
最近鉴定的G蛋白偶联受体的Mas相关基因（Mrg）家族几乎仅在背根神经节（DRG）神经元中表达。一个家族成员MrgD的表达甚至进一步局限于IB 4（+）、非肽能、小直径伤害感受器。虽然MrgD激活的功能后果尚不清楚，但这种表达谱提供了在疼痛感觉或调节中发挥作用的有趣潜力。在重组细胞系中，我们首先通过共表达MrgD与KCNQ 2/3钾通道（一种与疼痛有关的通道）来评估MrgD激活的功能意义。全细胞电压钳记录显示，浴应用MrgD的配体，β-丙氨酸，导致KCNQ 2/3活性的强烈抑制。G（i/o）和磷脂酶C信号的药理学阻断分别显示了部分和完全阻断反应。我们通过检查MrgD对M电流的调制（主要由KCNQ 2/3携带）将这些观察结果扩展到分离的DRG神经元培养物。在这里，β-丙氨酸诱导的内源性MrgD激活抑制M-电流，但主要是通过百日咳毒素敏感的途径。最后，我们评估了β-丙氨酸诱导的MrgD在相位神经元中激活的后果。在β-丙氨酸应用之前激发单个动作电位（AP）的相神经元在β-丙氨酸暴露期间激发多个AP。总之，我们提供的证据MrgD和KCNQ/M型钾通道之间的一种新的相互作用，有助于增加DRG神经元的兴奋性，从而可能增强初级传入伤害性神经元的信号。
The recently identified Mas-related gene (Mrg) family of G-protein-coupled receptors is expressed almost exclusively in dorsal root ganglion (DRG) neurons. The expression of one family member, MrgD, is even further confined to IB4(+), nonpeptidergic, small-diameter nociceptors. Although the functional consequences of MrgD activation are not known, this expression profile provides intriguing potential for a role in pain sensation or modulation. In a recombinant cell line, we first assessed the functional significance of MrgD activation by coexpressing MrgD with the KCNQ2/3 potassium channel, a channel implicated in pain. Whole-cell voltage-clamp recordings revealed that bath application of the ligand for MrgD, beta-alanine, resulted in robust inhibition of KCNQ2/3 activity. Pharmacological blockade of G(i/o) and phospholipase C signaling revealed a partial and complete block of the response, respectively. We extended these observations to dissociated DRG neuron cultures by examining MrgD modulation of M-currents ( carried primarily by KCNQ2/3). Here too, beta-alanine-induced activation of endogenous MrgD inhibited M-currents, but primarily via a pertussis toxin-sensitive pathway. Finally, we assessed the consequence of beta-alanine-induced activation of MrgD in phasic neurons. Phasic neurons that fired a single action potential (AP) before beta-alanine application fired multiple APs during beta-alanine exposure. In sum, we provide evidence for a novel interaction between MrgD and KCNQ/M-type potassium channels that contributes to an increase in excitability of DRG neurons and thus may enhance the signaling of primary afferent nociceptive neurons.