In the March issue of the Journal of General Physiology, Emily Pratt, a doctoral student in the Show-ling Shyng lab and primary author of “N-terminal transmembrane domain of SUR1 controls gating of Kir6.2 by modulating channel sensitivity to PIP2,” reveals new understanding of an important component involved in insulin secretion.
Pratt’s research focuses on the ATP-sensitive potassium (KATP) channel, a molecule involved in multiple physiologicalfunctions, including the regulation of insulin secretion. The KATP channel acts like a molecular gate, allowing potassium ions to cross cell membranes, but only in the presence of ATP, the energy unit of the cell. KATP channels are very complex proteins with eight subunits, formed by two proteins that make up the channel, (Kir6.2) and sulfonylurea receptor 1 (SUR1). Mutations in these two proteins may lead to rare but severe insulin secretion diseases in newborns and also contribute to more common forms of diabetes.
To understand how these mutations cause deregulation of insulin secretion, the researchers in Dr. Shyng’s lab attempt to identify the molecular defects that underlie these mutations and contribute to dysfunction of the channel. The research presented in this paper improves scientific understanding of how the two proteins that make up KATP interact with each other, as well as how other molecular components affect channel function.
Pratt’s research identifies a specific role for SUR1, the regulatory subunit of KATP, in proper function of the KATP channel. Pratt and her colleagues investigated two mutations that are known to cause congenital hyperinsulinism, or excessive insulin secretion in infants. This condition, depending on the severity, can result in multiple symptoms, including seizures and developmental delay. Most genetic mutations known to cause this disease directly affect the SUR1 subunit. Pratt’s research described a new mechanism by which SUR1 mutations may cause the disease: disruption of KATP’s ability to bind a molecule called PIP2, therefore affecting the ability of the channel to stay open. Because of the lack of information known about how the two subunits of the channel interact, this research represents a novel finding in the understanding of how insulin secretion is regulated.