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

TRPA1 is a Ca²⁺-permeable ion channel involved in many sensory disorders such as pain, itch and neuropathy. Notably, the function of TRPA1 depends on Ca²⁺, with low Ca²⁺ potentiating and high Ca²⁺ inactivating TRPA1. However, it remains unknown how Ca²⁺ exerts such contrasting effects. Here, we show that Ca²⁺ regulates TRPA1 through calmodulin, which binds to TRPA1 in a Ca²⁺-dependent manner. Calmodulin binding enhanced TRPA1 sensitivity and Ca²⁺-evoked potentiation of TRPA1 at low Ca²⁺, but inhibited TRPA1 sensitivity and promoted TRPA1 desensitization at high Ca²⁺. Ca²⁺-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 Ca²⁺ sensor enabling TRPA1 to respond to diverse Ca²⁺ signals distinctly.