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.
","abstract_html":"<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<sup>+</sup> conductance) is an interesting subfamily of K<sup>+</sup> channels responsive to both membrane voltage and intracellular calcium ion. The unique, high-affinity Ca<sup>2+</sup> sensitivity of BK channels is critical to their physiological function in various cell types. The mechanism by which Ca<sup>2+</sup> 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 Ca<sup>2+</sup>-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<sup>+</sup> 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 Ca<sup>2+</sup>-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 Ca<sup>2+</sup> activation: the Ca<sup>2+</sup>-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 Ca<sup>2+</sup> activation in BK channels.</p>","abstract_has_math":false,"creators":["Pico, Alexander R"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Thesis","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Roderick MacKinnon"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2003,"date_issued":"2003-01-01T08:00:00Z","date_published":"2003-01-01T08:00:00Z","updated_at":"2026-07-24T04:10:47Z","subjects":["ion channels","BK channels","Ca2+","K+","RCK domains","Life Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/44","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Roderick MacKinnon"]},{"key":"dc:creator","label":"Author","values":["Pico, Alexander R"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"thesis:degree_level","label":"Degree Level","values":["Thesis"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["ion channels","BK channels","Ca2+","K+","RCK domains","Life Sciences"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/44"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.
"]},{"key":"dc:title","label":"Title","values":["RCK Domain Model of Calcium Activation in BK Channels"]}]}],"canonical_facts":{"dc:contributor":["Roderick MacKinnon"],"dc:creator":["Pico, Alexander R"],"dc:description.abstract":["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.
"],"dc:identifier":["https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/44"],"dc:subject":["ion channels","BK channels","Ca2+","K+","RCK domains","Life Sciences"],"dc:title":["RCK Domain Model of Calcium Activation in BK Channels"],"thesis:degree_level":["Thesis"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T04:10:47Z"}