RCK Domain Model of Calcium Activation in BK Channels

<p>Potassium ion channels are ubiquitously expressed from bacteria to mammals where they are involved in various processes ranging from the regulation of osmotic pressure in a single cell to the electrical response in muscle fibers to the generation of action potentials in neurons. The BK channel family (BK for Big K⁺ conductance) is an interesting subfamily of K⁺ channels responsive to both membrane voltage and intracellular calcium ion. The unique, high-affinity Ca²⁺ sensitivity of BK channels is critical to their physiological function in various cell types. The mechanism by which Ca²⁺ activates BK channel gating, however, is not well understood. Here we present a structure-based approach to the study of BK channels with the goal of providing a structural and functional model of the Ca²⁺-activation mechanism. Sequence analysis of BK channel C-terminal domains and domains from prokaryotic homologs reveals the conservation of unique positions defining a novel regulatory domain associated with K⁺ conduction, the RCK domain. Crystal structures of RCK domains from prokaryotic sources relate the conservation of sequence to the structure, assembly and function of these domains. We propose a hypothetical model for the structure and function of the C-terminal domains of BK as a set of RCK domains that conduct the Ca²⁺-activation mechanism. The features and constraints predicted by the RCK domain model are tested by the electrophysiological assay of a variety of human BK constructs. The results support a domain structure and assembly consistent with the proposed model for the BK C-terminus. In addition, the results identify residues and regions involved in Ca²⁺ activation: the Ca²⁺-binding event and the transduction of the binding energy through protein conformational changes to the channel domain. The RCK domain model thus provides a framework for the study of Ca²⁺ activation in BK channels.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Thesis

Year

2003

Author dc:creator

• Pico, Alexander R

Contributors dc:contributor

• Roderick MacKinnon

• ion channels
• BK channels
• Ca2+
• K+
• RCK domains
• Life Sciences

Repository record dc:identifier

https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/44

OAI identifier oai:identifier

oai:digitalcommons.rockefeller.edu:student_theses_and_dissertations-1043