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.
School of Medicine, Medical Sciences &Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom.|Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.|Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, United Kingdom.
Raquibul
R
Hasan
School of Medicine, Medical Sciences &Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom.
Alasdair T S
AT
Leeson-Payne
Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Jonathan H
JH
Jaggar
School of Medicine, Medical Sciences &Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, United Kingdom.|Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, United Kingdom.|Schcool of Life &Health Sciences, Aston University, Aston triangle, Birmingham B4 7ET, United Kingdom.
Xuming
X
Zhang