Sigworth Laboratory  

 

 

Department of Cellular and Molecular Physiology

Yale School of Medicine     BBS

 


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Ion channels
Work in our laboratory centers on the function and structure of ion channel proteins. Ion channels are molecular transducers that switch on and off electrical currents that are carried by ions across biological membranes. Depending on the ion channel type, the switching action is controlled by voltage, mechanical forces, or the binding of particular small molecules (ligands). We call these channels voltage-gated, mechanosensitive and ligand-gated channels, respectively. Voltage-gated channels act as "life's transistors" as you can read in a recent short article.

 

Mechanisms of gating
We are particularly interested in the switching mechanisms of channels. What is the molecular machinery, and how does it work, that switches on an ion current in response to a voltage change or the binding of a ligand? One approach is to take pictures of channel proteins in their open and closed states. We are

Slack Recording

Recording of Slack channel current

pursuingthis through the use of high-resolution electron microscopy. Another approach is to study the switching activity of both normal and modified channels by recording the ionic currents. The patch clamp technique allows single channel currents to be measured with high precision. The molecular motions involved in the sensing and switching can also be studied by fluorescence techniques. Here changes in distances result in changes in the spectrum of light emitted from pairs of fluorescent molecules.

Our favorite channels

IP3 receptor


Our work concerns a few particular channel types. One is a voltage-gated potassium channel, called Shaker after the name of a misbehaving fruit fly that lacks this channel's gene. Another is a member of the same voltage-gated channel family, but is also controlled by ligands, namely calcium ions. When open it allows a large current of potassium ions to flow, and so is known as the BK (big K+) channel. The third is an intracellular calcium-release channel called the IP3 receptor. It opens in response to the binding of an important intracellular messenger molecule, inositoltrisphosphate, and releases calcium ions from intracellular stores.

Technology development
Patch-Clamp Advances in biology come from advances in instrumentation and techniques. We are working in two areas of technology development.We are developing fully integrated patch-clamp amplifier systems that would facilitate the fabrication of automatic, high-throughput recoriding systems that can patch 384 or more cells in parallel. To simplify the structure determination of membrane proteins (such as ion channels) we are pursuing technical advances in electron microscopy of frozen single-molecule specimens (single-particle cryo-EM) and the mathematical reconstruction of 3D structures from electron microscope images.

S1Die
Integrated Two-Channel Patch-Clamp System

 

 

 

 

 

     

 

 

 

 


Last modified: January 28, 2011 YY.

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