Author's School

School of Engineering & Applied Science

Author's Department/Program

Energy, Environmental and Chemical Engineering

Language

English (en)

Date of Award

January 2011

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Jianmin Cui

Abstract

The large conductance voltage- and Ca2+-activated K+: BK) channel is important for many physiological functions. The BK channel is activated by both membrane depolarization and intracellular Ca2+ so that it integrates these two important cellular signals. Ca2+ sensing of the BK channel is mediated by two binding sites, both located on the cytosolic domain. The structure of the cytosolic domain indicates that both binding sites are away from the pore-gate domain, suggesting that a coupling mechanism between the binding sites and the gate is required for Ca2+-dependent activation. The work in this dissertation focuses on the coupling mechanism, which can be divided into two steps. The first step of the coupling mechanism is within the cytosolic domain and mediated by the AC region, which is on top of the cytosolic domain and adjacent to the membrane. The coupling mechanism of the AC region is regulated by its dynamics, which can be altered by either the disease-associated mutation D369G or changes in solution viscosity. The second step of the coupling mechanism transmits Ca2+ binding energy across the interface between the cytosolic and membrane-spanning domains, which is found in the form of relative movements between these two domains. Using an electrostatic interaction between the two domains, we further show that the relative movements may be the coupling mechanism for both voltage- and Ca2+-dependent activation pathways. Therefore, we have revealed novel properties of the coupling mechanism for Ca2+-dependent activation in BK channels. Our findings are particularly important for understanding the structure-function relationship of the BK channel.

DOI

https://doi.org/10.7936/K73B5X6C

Comments

Permanent URL: http://dx.doi.org/10.7936/K73B5X6C

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