Calmodulin is responsible for Ca2+-dependent regulation of TRPA1 Channels

TRPA1 is a Ca 2+ -permeable ion channel involved in many sensory disorders such as pain, itch and neuropathy. Notably, the function of TRPA1 depends on Ca 2+ , with low Ca 2+ potentiating and high Ca 2+ inactivating TRPA1. However, it remains unknown how Ca 2+ exerts such contrasting effects. Here, we show that Ca 2+ regulates TRPA1 through calmodulin, which binds to TRPA1 in a Ca 2+ -dependent manner. Calmodulin binding enhanced TRPA1 sensitivity and Ca 2+ -evoked potentiation of TRPA1 at low Ca 2+ , but inhibited TRPA1 sensitivity and promoted TRPA1 desensitization at high Ca 2+ . Ca 2+ -dependent potentiation and inactivation of TRPA1 were selectively prevented by disrupting the interaction of the carboxy-lobe of calmodulin with a calmodulin-binding domain in the C-terminus of TRPA1. Calmodulin is thus a critical Ca 2+ sensor enabling TRPA1 to respond to diverse Ca 2+ signals distinctly.