Grant: CIHR New Investigator

Many diseases are caused by a disruption of mechanisms that regulate voltage across cell membranes. The most frequent culprits in these 'membrane excitability disorders' are proteins with 'transporter' or 'channel' functions. Our research is focused on ion channel proteins, which form pores in cell membranes that allow charged ions to pass through, generating electrical currents and influencing the membrane voltage. Much like household lights, these ion channel proteins can be switched on or off, by opening or closing 'gates' in the ion-conducting pore, and the mechanisms that control this process are collectively referred to as 'gating'. We are currently studying a family of ion channels known as inwardly-rectifying potassium (Kir) channels, which regulate diverse processes, from beating of the heart, to hormone release. Recent studies have linked genetic mutations in Kir channels to cardiac arrhythmias, vascular defects, and severe disorders including Andersen's syndrome, Bartter's syndrome, and DEND (Diabetes with Epilepsy and Neuromuscular Defects), demonstrating a broad spectrum of physiological roles of these channels. Our focus is the KATP channel - a remarkable Kir channel type that is regulated by the 'fuel' (ATP) that drives all cells, and is therefore a sensor for the metabolic state. These channels generate an electrical signal correlated with cellular metabolism, and this serves as a critical trigger for insulin release from pancreatic beta-cells. KATP channel mutations are recognized as an important cause of (and therapeutic target for) genetically inherited insulin disorders, ranging from diabetes (too little insulin released) to hyperinsulinism (too much insulin). Additionally, KATP channels are the most densely expressed potassium channel in the heart, but their cardiovascular function remains enigmatic and controversial, underscoring the need for further investigation of regulatory mechanisms of this ion channel type.