Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
J Biol Chem. 2012 Aug 3;287(32):27087-94. doi: 10.1074/jbc.M112.341776. Epub 2012 Jun 4.
The role of genetic modifications of the TRPA1 receptor has been well documented in inflammatory and neuropathic pain. We recently reported that the E179K variant of TRPA1 appears to be crucial for the generation of paradoxical heat sensation in pain patients. Here, we describe the consequences of the single amino acid exchange at position 179 in the ankyrin repeat 4 of human TRPA1. TRPA1 wild type Lys-179 protein expressed in HEK cells exhibited intact biochemical properties, inclusive trafficking into the plasma membrane, formation of large protein complexes, and the ability to be activated by cold. Additionally, a strong increase of Lys-179 protein expression was observed in cold (4 °C) and heat (49 °C)-treated cells. In contrast, HEK cells expressing the variant Lys-179 TRPA1 failed to get activated by cold possibly due to the loss of ability to interact with other proteins or other TRPA1 monomers during oligomerization. In conclusion, the detailed understanding of TRPA1 genetic variants might provide a fruitful strategy for future development of pain treatments.
TRPA1 受体的遗传修饰在炎症和神经性疼痛中作用已得到充分证实。我们最近报道称，TRPA1 的 E179K 变体似乎对疼痛患者产生矛盾的热感觉至关重要。在这里，我们描述了人 TRPA1 的锚蛋白重复 4 中第 179 位单个氨基酸交换的后果。在 HEK 细胞中表达的野生型 TRPA1Lys-179 蛋白表现出完整的生化特性，包括易位到质膜、形成大的蛋白质复合物以及被冷激活的能力。此外，在冷（4°C）和热（49°C）处理的细胞中观察到 Lys-179 蛋白表达的强烈增加。相比之下，表达变体 Lys-179 TRPA1 的 HEK 细胞可能由于在寡聚化过程中丧失与其他蛋白质或其他 TRPA1 单体相互作用的能力而无法被冷激活。总之，对 TRPA1 遗传变异的深入了解可能为未来的疼痛治疗提供一种有成效的策略。
