Abstract
The small ubiquitin-like modifier (SUMO) protein pathway governs a panoply of vital biological processes including cell death, proliferation, differentiation, metabolism, and signal transduction by diversifying the functions, half-lives, and partnerships of target proteins in situ. More recently, SUMOylation has emerged as a key regulator of ion homeostasis and excitability across multiple tissues due to the regulation of a plethora of ion channels expressed in a range of tissue subtypes. Altogether, the balance of SUMOylation states among relevant ion channels can result in graded biophysical effects that tune excitability and contribute to a range of disease states including cardiac arrhythmia, epilepsy, pain transmission, and inflammation. Here, we consolidate these concepts by focusing on the role of ion channel SUMOylation in the central nervous system, peripheral nervous system, and cardiovascular system. In addition, we review what is known about the enigmatic factors that regulate the SUMO pathway and consider the emerging role of small molecule SUMO modulators as potential therapeutics in a range of diseases.