Therapeutic Potential of Targeting Regulated Intramembrane Proteolysis Mechanisms of Voltage-Gated Ion Channel Subunits and Cell Adhesion Molecules

Several integral membrane proteins undergo regulated intramembrane proteolysis (RIP), a tightly controlled process through which cells transmit information across and between intracellular compartments. RIP generates biologically active peptides by a series of proteolytic cleavage events carried out by two primary groups of enzymes: sheddases and intramembrane-cleaving proteases (iCLiPs). Following RIP, fragments of both pore-forming and non-pore-forming ion channel subunits, as well as immunoglobulin super family (IgSF) members, have been shown to translocate to the nucleus to function in transcriptional regulation. As an example, the voltage-gated sodium channel beta 1 subunit, which is also an IgSF-cell adhesion molecule (CAM), is a substrate for RIP. beta 1 RIP results in generation of a soluble intracellular domain, which can regulate gene expression in the nucleus. In this review, we discuss the proposed RIP mechanisms of voltage-gated sodium, potassium, and calcium channel subunits as well as the roles of their generated proteolytic products in the nucleus. We also discuss other RIP substrates that are cleaved by similar sheddases and iCLiPs, such as IgSFmacromolecules, including CAMs, whose proteolytically generated fragments function in the nucleus. Importantly, dysfunctional RIP mechanisms are linked to human disease. Thus, we will also review how understandingRIP events and subsequent signaling processes involving ion channel subunits and IgSF proteins may lead to the discovery of novel therapeutic targets.