I received my Ph.D. from University of California, Davis, in pharmacology and toxicology, and did my postdoctoral work in biophysics at the University of Rochester in Rochester, NY, where I worked on cardiac Ca channels. After my postdoc, I worked in the pharmaceutical industry for eight years (Searle, Merck) to discover new antiarrhythmic agents. The last 13 years have been spent at the University of Utah, where my research has focused on inherited arrhythmias and K+ channel pharmacology.

Attempting to discover and characterize antiarrhythmic drugs at Merck and studying the biophysics of mutant channels that cause inherited long QT syndrome.

The lab has three ongoing ion channel biophysics projects. First, to characterize the physiological consequences of mutations in cardiac K+ and Ca2+ channels that cause inherited arrhythmia. Second, to map the binding site for drugs that block or activate K+ channels. Third, to explore the molecular mechanisms of coupling between voltage sensing and channel opening in hERG and HCN pacemaker channels.

Prior to this work, it was known that expression of minK subunits in Xenopus oocytes induced a slowly activating K+ current with properties very similar to the cardiac slow delayed rectifier K+ current (IKs); however, expression in mammalian cells did not induce any current. The KVLQT1 gene (now more commonly called KCNQ1) was discovered by Mark Keating's group at Utah during a search for gene mutations that cause a particular form of inherited long QT syndrome (LQT1). Soon after this gene was cloned, I guessed that it might be the partner of minK that when co-assembled would form channels that conducted IKs. This turned out to be true. (Oocytes constitutively express a homolog of the human KVLQT1 and hence were able to form channels when only minK cRNA was injected into these cells). The importance of the work is that it provided the molecular basis for IKs and also predicted that mutations in minK would also cause inherited long QT syndrome—a prediction that was confirmed a year later.

hERG was first cloned by Jeff Warmke and Barry Ganetsky (University of Wisconsin) from a human hippocampus cDNA library based on its homology with a related Drosophila gene (EAG). We and others (Gail Robertson's group at the University of Wisconsin) independently expressed the channel in oocytes and discovered that the channel had properties remarkably similar to the cardiac rapid delayed rectifier K current (IKr). I had earlier (1990) described IKr, and differentiated it from IKs, in myocytes by a pharmacological approach—IKr was blocked by several antiarrhythmic drugs, whereas IKs was not. It was wonderful to have both channel types described at a molecular level just five years after their initial separation in guinea pig myocytes.

Hopefully, a better understanding of how drugs block the hERG channel will enable or facilitate in silico efforts to design drugs that do not block the channel. This side effect has really slowed down the drug discovery process. We are also currently trying to understand how hERG channel activators affect gating and increase channel conductance. These drugs might be useful to treat long QT syndrome.

Michael C. Sanguinetti, Ph.D.
University of Utah, CVRTI
Salt Lake City, UT, USA