Role Of Lipid Raft Domains In Assembly And Regulation Of Store-operated Calcium Entry Channels

Abstract

Plasma membrane lipid raft domains (LRD) serve as platforms for the assembly of signaling complexes, including Ca2+ signaling proteins. Such assembly determines the specificity and rate of interaction between the proteins. Previously, we have reported that (i) TRPC1 is associated with LRD, and (ii) intact LRDs are required for SOCE in salivary gland cells. Recently, Orai1 and STIM1 have been identified as key components of TRPC1-SOC channels. While the role of Orai1 is not fully elucidated as yet, STIM1 is a Ca2+-binding ER resident protein that relays the store depletion signal to the plasma membrane channels. It is now well established that STIM1 aggregates in response to store depletion and translocates to the ER-PM junctional domains which are proposed to be the sites where this protein interacts with and activates channels mediating SOCE. In our recent studies, we have assessed the mechanisms that determine targeting of STIM1 and its clustering with TRPC1. Our dat demonstrate that anchoring of STIM1 in the subplasma membrane region of the cell and activation of TRPC1-dependent SOCE are determined by LRD. These findings and others describing scaffolding of TRPC1 in LRD will be discussed. Together with our studies demonstrate that orchestration of precise and dynamic assembly of SOC channels allows compartmentalization of Ca2+ entry signals, which is critical for regulating specific downstream signaling events that are critical for cell function.