The goal of this work is to determine how voltage-gated potassium (Kv) channels are controlled by KCNE subunits. Also called MinK-related peptides (MiRPs), these single-pass transmembrane accessory subunits merit investigation because they are required for normal function of the heart and other organs that depend on Kv channels. MiRPs exert their powerful effects by assembly with Kv channel pore-forming subunits and thereby direct location and level, voltage-sensitivity, time- dependence, unitary conductance, ion selectivity, and response to regulators and pharmaceuticals. Identifying and studying MiRPs has advanced diagnosis and treatment of cardiac disease. The significance of this application is two-fold. First, we have learned a great deal about what MiRPs do in the heart over the last decade but not yet how they do it. Second, tools are now available to delineate conformational dynamics, that is, the mechanistic basis for protein operation in real-time. Here, powerful optical, electrophysiological and modeling techniques are brought to bear on channels as they form in cells, a capability unimaginable just a decade ago. The result is no less than this: we can now answer basic, outstanding questions in human physiology and disease. The three aims focus on operation of two important channels formed by the same pore-forming Kv subunit (Kv7.1 = KCNQ1 = Q1) and two different MiRPs (MinK = E1 and MiRP2 = E3). The study addresses questions at the core of physiology. To wit: why does IKs (Q1 + E1) in the heart and ear respond slowly to voltage? How does IK (Q1 + E3) found in heart and colon react instantaneously to voltage? These normal functions are disrupted by inherited differences and acquired disease. More basically, the study can reveal key principles of operation of voltage sensors and gates and the impact of accessory subunits;these insights have relevance throughout the body.
Voltage-gated potassium (Kv) channels are essential to normal activity of the human heart;pore-forming and KCNE subunits combine to build channels in the correct location, at the appropriate level of activity, and with proper responsiveness to the environment (for example, exercise and medicines). Inherited differences in the subunits place some persons at risk for disease. Understanding how these channels operate has advanced health maintenance and will continue to improve the diagnosis and treatment of diseases of the cardiovascular system and other organs throughout the body.
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|Plant, Leigh D; Xiong, Dazhi; Dai, Hui et al. (2014) Individual IKs channels at the surface of mammalian cells contain two KCNE1 accessory subunits. Proc Natl Acad Sci U S A 111:E1438-46|
|Silva, Jonathan R; Goldstein, Steve A N (2013) Voltage-sensor movements describe slow inactivation of voltage-gated sodium channels II: a periodic paralysis mutation in Na(V)1.4 (L689I). J Gen Physiol 141:323-34|
|Silva, Jonathan R; Goldstein, Steve A N (2013) Voltage-sensor movements describe slow inactivation of voltage-gated sodium channels I: wild-type skeletal muscle Na(V)1.4. J Gen Physiol 141:309-21|
|Ruscic, Katarina J; Miceli, Francesco; Villalba-Galea, Carlos A et al. (2013) IKs channels open slowly because KCNE1 accessory subunits slow the movement of S4 voltage sensors in KCNQ1 pore-forming subunits. Proc Natl Acad Sci U S A 110:E559-66|
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