About the Lab
Our research focuses on mechanisms that govern the opening and closing (gating) of ion channels. Ion channels are transmembrane proteins that transduce stimuli such as membrane voltage or ligand-binding into electrochemical signals by opening and closing to regulate membrane permeability. In this way channels mediate electrical and chemical signaling that is crucial to the function of nerve, muscle, and other cell types. Thus an understanding of ion channel gating has broad consequences for understanding normal cell function, disease and therapeutic mechanisms. We are particularly interested in the physical basis of channel gating, how multiple stimuli and regulatory factors interact to determine channel activity, and how drugs regulate this process.
For an ion channel to transduce signals it must contain sensors to detect stimuli, a gate to control the flow of ions through an ion-selective pore, and mechanisms that couple sensors to the gate. Sensor, gate and pore domains have been identified in many channels, and much is known about their structure and function. However, the mechanisms by which sensors and gates communicate represent a key aspect of channel gating that remains in many ways poorly understood. Therefore an important goal of our research has been to determine the functional properties and molecular basis of sensor/gate communication and how it is regulated.
To understand how sensors and gates communicate we study the large conductance Ca2+-activated K+ (BK) channel; a channel that senses both membrane voltage and intracellular calcium. BK channels play a role in many physiologically important processes including synaptic transmission and the regulation of vascular smooth muscle tone, and have been targeted therapeutically to treat conditions such as hypertension, stroke and asthma. We find that the functional coupling between voltage sensor activation, Ca2+-binding, and channel opening can be described in terms of allosteric mechanisms. We are studying the molecular basis of these interactions. We are also investigating how drugs and endogenous modulators of channel function such as intracellular Mg2+ , heme and transition metal ions affect gating processes controlled by voltage and Ca2+. We seek to establish a comprehensive understanding of BK channel regulation that may serve as a basis for understanding disease mechanisms and developing more effective therapeutic options.
Techniques employed in the lab include, but are not limited to, patch clamp electrophysiology, site-directed mutagenesis, the substituted cysteine accessibility method (SCAM), and computer modeling of channel gating.
