IP3 receptor processing by the ERAD pathway

Abstract

Inositol 1,4,5‐trisphosphate (IP3) receptors are large ER membrane proteins which form tetrameric channels that govern the release of Ca2+ stored within the ER lumen of vertebrate cells. They are named for their ability to bind to and be opened by the second messenger IP3, which is generated at the plasma membrane in response to cell surface receptor activation. Thus, IP3 receptors are pivotal in signaling pathways that couple extracellular hormones, neurotransmitters and growth factors to increases in cytoplasmic Ca2+ concentration and the regulation of Ca2+‐dependent events (e.g. secretion, fertilization, apoptosis and gene expression). Surprisingly, when IP3 receptors are activated they are rapidly destroyed via the ER‐associated degradation (ERAD) pathway, a ubiquitination‐and proteasome‐dependent mechanism that clears the ER of aberrant proteins. I will review recent studies aimed at identifying which ERAD pathway components mediate IP3 receptor ERAD, focusing on a novel complex composed of the ER membrane proteins erlin 1 and 2 which binds to IP3 receptors immediately after they are activated, and the E3 ligase RNF170, which participates in IP3 receptor ubiquitination.