Calmodulin is responsible for Ca-dependent regulation of TRPA1 Channels.

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