The KCNQ1 voltage gated K+ channel is expressed in many different tissues and plays widely different roles in these different tissues. Mutations and polymorphisms in KCNQ1 have been implicated in multiple diseases, including cardiac arrhythmias, inherited deafness, and susceptibility to type 2 diabetes. In the heart, KCNQ1 is co-expressed with the beta subunit KCNE1 to form the slowly activating, voltage gated IKs channels that contribute critically to the repolarization of the cardiac action potential at the cellular level and the QT interval of the electrocardiogram. In other cell types, such as epithelia and kidney cells, KCNQ1 is co-expressed with the beta subunits KCNE2 or KCNE3 to form a voltage independent K+ channel that is important for K+ and Cl- secretion. The critical role of KCNQ1 has been revealed by inherited mutations which have been associated with such diverse cardiac rhythm disturbances as the Long QT syndrome, the Short QT Syndrome, and atrial fibrillation. In many cases, co-assembly with the KCNE1 subunit dictates pathological function. How different beta subunits and mutations alter the function of KCNQ1 channels is not completely understood. We will here simultaneously measure the movement of the voltage sensor and the activation gate in KCNQ1 channels. This will allow us to determine whether a specific beta subunit or mutation mainly affects the voltage sensor or the gate. We will also test the effects of different modulators, both activators and inhibitors, of KCNQ1 on the voltage sensor movement and the activation gate, in order to understand how these molecules affect KCNQ1 activity and whether these molecules can restore the function of mutant KCNQ1 channels. The completion of these aims will generate a better understanding of how KCNE beta subunits modulate KCNQ1 channel functions, how small molecule modulators affect KCNQ1 channels, and how the defects of disease- causing KCNQ1 mutations can be overcome in a mutation- and small molecule dependent manner. This would be a first step in generating mutation specific treatments of diseases, such as cardiac arrhythmias, caused by mutations in KCNQ1.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM109762-04
Application #
9189637
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nie, Zhongzhen
Project Start
2014-05-01
Project End
2018-12-31
Budget Start
2017-01-01
Budget End
2018-12-31
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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