Crozier Robert A, Ajit Seena K, Kaftan Edward J, Pausch Mark H
Wyeth Research, Discovery Neuroscience, CN 8000, Princeton, New Jersey 08543-8000, USA.
J Neurosci. 2007 Apr 18;27(16):4492-6. doi: 10.1523/JNEUROSCI.4932-06.2007.
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.
最近发现的与Mas相关的G蛋白偶联受体基因（Mrg）家族几乎只在背根神经节（DRG）神经元中表达。其中一个家族成员MrgD的表达甚至进一步局限于IB4 +、非肽能、小直径伤害感受器。尽管MrgD激活的功能后果尚不清楚，但这种表达模式为其在痛觉或调节中的作用提供了有趣的可能性。在一个重组细胞系中，我们首先通过将MrgD与KCNQ2/3钾通道共表达来评估MrgD激活的功能意义，KCNQ2/3钾通道与疼痛有关。全细胞膜片钳记录显示，向浴槽中加入MrgD的配体β-丙氨酸，可强烈抑制KCNQ2/3的活性。对G(i/o)和磷脂酶C信号的药理学阻断分别显示了对该反应的部分和完全阻断。我们通过检查MrgD对M电流（主要由KCNQ2/3携带）的调节，将这些观察结果扩展到解离的DRG神经元培养物中。同样，β-丙氨酸诱导的内源性MrgD激活也抑制了M电流，但主要是通过百日咳毒素敏感途径。最后，我们评估了β-丙氨酸诱导的MrgD激活在相位性神经元中的后果。在施加β-丙氨酸之前发放单个动作电位（AP）的相位性神经元，在β-丙氨酸暴露期间发放多个AP。总之，我们提供了证据表明MrgD与KCNQ/M型钾通道之间存在新的相互作用，这有助于增加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传递。
