Calmodulin is responsible for Ca(2+)-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.