KCNQ Ion channel conformation change by calmodulin and impact on human disease

Chang, Aram

Abstract

The long-term goal of this project is to understand ion channel structures and function and its impact to heart and nervous diseases. KCNQ (Kv7) is a voltage-gated potassium channel, which is important in heart, vestibular, auditory, and neuronal function. A number of mutations in KCNQ disrupt ion channel functions and lead to various diseases such as cardiac arrhythmias, deafness, and epilepsy. Among five isoform of KCNQ, KCNQ1 is strongly related to the long QT syndrome (LQTS), which is a heart rhythm disorder with heartbeat increases and leads to palpitation, fainting and sudden death. Also, KCNQ2 and KCNQ3 are related to the benign familial neonatal seizures (BFNS), a rare autosomal dominant epilepsy form of infants. Some of these mutations are proposed to impair proper association of auxiliary molecules to KCNQ, which make KCNQ unable to respond to the signal from outside. One of the principal signaling biomolecule for the KCNQ function is calmodulin (CaM), which is a universal calcium-signal sensor in biology. It has been proposed that calcium ion will convert apo-CaM to Ca2+/CaM, which will trigger the conformational change and flexibility of the KCNQ C-terminal domain and functional modulation. To understand KCNQ channel function modulation by calmodulin, I would like to propose structural, biophysical, and functional approaches. This proposal will investigate the KCNQ cytoplasmic C-terminal region with CaM complex structure using X-ray crystallography and small angle X-ray scattering and biophysical role of known disease mutants for CaM binding to KCNQ using isothermal titration calorimetry. The outcome from this proposal would improve our understanding of ion channel function and provide insight for the KCNQ related disease therapeutic treatments.

Public Health Relevance

Voltage-gated ion channels (VGIC) are key component proteins in heart and neuron functions and major drug targets for cardiac arrhythmia, deafness, epilepsy, pain, and mood disorder. This proposal aims to provide the structural and functional basis of voltage-gated potassium ion channel to understand related disease mechanisms, such as heart disease (long QT syndrome), deafness, and epilepsy (BFNS), which will contribute to development of cardiac and nervous disease treatments.