Biomedical subjects

Medha M Pathak

Publications and source records attributed to Medha M Pathak.

4 recordsLinked to original sources

PubMed2006

The twisted ion-permeation pathway of a resting voltage-sensing domain.

Proteins containing voltage-sensing domains (VSDs) translate changes in membrane potential into changes in ion permeability or enzymatic activity. In channels, voltage change triggers a switch in conformation of the VSD, which drives gating in a separate pore domain, or, in channels lacking a pore domain, directly gates an ion pathway within the VSD. Neither mechanism is well understood. In the Shaker potassium channel, mutation of the first arginine residue of the S4 helix to a smaller uncharged residue makes the VSD permeable to ions ('omega current') in the resting conformation ('S4 down'). Here we perform a structure-guided perturbation analysis of the omega conductance to map its VSD permeation pathway. We find that there are four omega pores per channel, which is consistent with one conduction path per VSD. Permeating ions from the extracellular medium enter the VSD at its peripheral junction with the pore domain, and then plunge into the core of the VSD in a curved conduction pathway. Our results provide a model of the resting conformation of the VSD.

Animals↗

PubMed2006

How does voltage open an ion channel?

Neurons transmit information through electrical signals generated by voltage-gated ion channels. These channels consist of a large superfamily of proteins that form channels selective for potassium, sodium, or calcium ions. In this review we focus on the molecular mechanisms by which these channels convert changes in membrane voltage into the opening and closing of "gates" that turn ion conductance on and off. An explosion of new studies in the last year, including the first X-ray crystal structure of a mammalian voltage-gated potassium channel, has led to radically different interpretations of the structure and molecular motion of the voltage sensor. The interpretations are as distinct as the techniques employed for the studies: crystallography, fluorescence, accessibility analysis, and electrophysiology. We discuss the likely causes of the discrepant results in an attempt to identify the missing information that will help resolve the controversy and reveal the mechanism by which a voltage sensor controls the channel's gates.

Animals↗

PubMed2005

How far will you go to sense voltage?

Despite tremendous progress in the study of voltage-gated channels, the molecular mechanism underlying voltage sensing has remained a matter of debate. We review five new studies that make major progress in the field. The studies employ a battery of distinct approaches that have the common aim of measuring the motion of the voltage sensor. We interpret the results in light of the recent crystal structure of the mammalian potassium channel Kv1.2. We focus on the transmembrane movement of the voltage sensor as a key element to the detection of membrane potential and to the control of channel gating.

Animals↗

PubMed2005

Voltage-sensing arginines in a potassium channel permeate and occlude cation-selective pores.

Voltage-gated ion channels sense voltage by shuttling arginine residues located in the S4 segment across the membrane electric field. The molecular pathway for this arginine permeation is not understood, nor is the filtering mechanism that permits passage of charged arginines but excludes solution ions. We find that substituting the first S4 arginine with smaller amino acids opens a high-conductance pathway for solution cations in the Shaker K(+) channel at rest. The cationic current does not flow through the central K(+) pore and is influenced by mutation of a conserved residue in S2, suggesting that it flows through a protein pathway within the voltage-sensing domain. The current can be carried by guanidinium ions, suggesting that this is the pathway for transmembrane arginine permeation. We propose that when S4 moves it ratchets between conformations in which one arginine after another occupies and occludes to ions the narrowest part of this pathway.

Amino Acid Substitution↗