Molecular cell biology of ion channels in health and disease

We recognize that ion channels are signaling proteins and that it is important that their levels at the cell surface are regulated in order to generate signals appropriate to the needs of a cell. Eukarytoic cells have evolved sophisticated mechanisms that regulate trafficking of ion channels to and out of the plasma membrane. From studies of inherited mutations we now know that disruption of these mechanisms leads to serious diseases. Using the strategy outlined in the schematic, we are studying two ion channels: the ATP-sensitive potassium (KATP) channel and the hERG potassium channel.

Hereditary mutations in ion channels to understand the molecular causes of disease

The KATP channel controls insulin secretion. Genetic mutations that affect the function or trafficking of this channel cause diseases of abnormal insulin secretion: permanent neonatal diabetes mellitus (PNDM) and congenital hyperinsulinism (CHI). Genome wide association studies demonstrated association of KCNJ11 (a gene encoding the pore forming subunit of the channel) with type-2 diabetes - a disease afflicting 150 million people worldwide, with a predicted increase to 300 millions in 2025.

Our aim is to understand how trafficking of this channel is controlled in a healthy cell and how trafficking is disrupted in a disease state. Towards this end, we have been using techniques in biochemistry, molecular cell biology and electrophysiology. We have recently started exploring the possibility of using cell penetrating peptides to regulate trafficking, and thereby the function of the channel; such approaches have the potential for development of new drugs. Our studies so far have demonstrated:

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Movement of KATP channels to and out of the plasma membrane. Live cell imaging.

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