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Ion channel gating kinetics and structure implication for drug delivery

Project Description

Ion channels are proteins which sit in the membrane of every cell in the body and control the flow of positively charged ions such as sodium and potassium into and out of the cell. The traditional view is that an ion channel exists in one of two stochastic states i.e. open or closed. However, this is challenged by the observation of intermediate conductance, or ’subconductance’, states in a number of ion channels, including several potassium (K+) channels.

In this study we propose to investigate subconductance states in heteromeric Kir4.1/Kir5.1 potassium channels by taking advantage of the fact that these particular channels exhibit long-lived subconductance states and that an ortholog of Kir5.1 from Xenopus tropicalis causes a dramatic change in the frequency and duration of these substates. Single-channel currents will be reconstructed by building a mathematical modelling. For the measurement of subconductance states in all type of channels we will use the threshold-crossing method, amplitude histograms and HMM (Hidden Markov Model) analysis. Single-channel events will be analysed first by idealising the recording into closed and open dwells, and then fitting histograms of dwell times with mixtures of exponential functions that reflect the dwells in various states using Clampfit 9.2 and HJCFIT software. To ensure the unambiguous detection of brief sublevel events and comparison of sublevel durations we will use QuB analysis software.

This information about channel gating would provide suggestion for ion channel drug delivery.

Funding Notes

This is a self-funded PhD project; applicants will be expected to pay their own fees or have a suitable source of third-party funding. A bench fee also applies in addition to tuition fees.

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