Even modest changes in voltage-gated ion channel expression levels can have large effects on the cellular electrophysiology and/or the calcium metabolism of electrically excitable cells. This can, in turn, destabilize organ function, producing epilepsies or arrhythmias. Not surprisingly, therefore, the level at which different ion channels are expressed in electrically excitable cells is tightly regulated by natural selection, just as the functional properties of the channels are subject to purifying selection.

Regulatory evolution is a broad category that encompasses the evolution of all the various mechanisms that can affect expression of a given protein. Regulatory evolution establishes the baseline expression levels of the different ion channels in each differentiated compartment of the heart. Evolution of a given gene’s promoter and of the various cis-regulatory modules that modulate the function of that promoter is known, more specifically, as cis-regulatory evolution. Baseline levels of voltage-gated ion channel expression appear to be predominantly determined at the level of transcription. Consequently, it is likely that cis-regulatory evolution will be a major factor determining tissue specific channel expression levels in the heart and we have described experimental evidence in support of this hypothesis (Yan et al., 2012).

We interested in the cis-regulatory function of voltage-gated ion channel genes, how they respond to disease states and how this regulatory function can evolve. We use comparative in vitro analysis of gene regulatory function and conditional gene knockouts to study this problem.