Endocytosis: A Turnover Mechanism Controlling Ion Channel Function

Abstract

Ion channels (IChs) are transmembrane proteins that selectively drive ions across membranes. The function of IChs partially relies on their abundance and proper location in the cell, fine-tuned by the delicate balance between secretory, endocytic, and degradative pathways. The disruption of this balance is associated with several diseases, such as Liddle’s and long QT syndromes. Because of the vital role of these proteins in human health and disease, knowledge of ICh turnover is essential. Clathrin-dependent and -independent mechanisms have been the primary mechanisms identified with ICh endocytosis and degradation. Several molecular determinants recognized by the cellular internalization machinery have been discovered. Moreover, specific conditions can trigger the endocytosis of many IChs, such as the activation of certain receptors, hypokalemia, and some drugs. Ligand-dependent receptor activation primarily results in the posttranslational modification of IChs and the recruitment of important mediators, such as β-arrestins and ubiquitin ligases. However, endocytosis is not a final fate. Once internalized into endosomes, IChs are either sorted to lysosomes for degradation or recycled back to the plasma membrane. Rab proteins are crucial participants during these turnover steps. In this review, we describe the major ICh endocytic pathways, the signaling inputs triggering ICh internalization, and the key mediators of this essential cellular process.

Profile of Membrane Cargo Trafficking Proteins and Transporters Expressed under N Source Derepressing Conditions in Aspergillus nidulans

“…Furthermore, eukaryotes seem to employ several points of protein quality control safeguarding that transporters are properly folded during the first steps of their initial biogenesis or remain structurally ‘undamaged’ under specific stress conditions. In case transporters are misfolded or damaged by chemical or physical stress or as a result of prolonged activity, cells employ processes such as endoplasmic reticulum-associated degradation (ERAD) and proteasome degradation, as well as specific chaperone-assisted selective autophagy [ 5 ] in addition to endocytosis, for driving transporter turnover [ 6 , 7 , 8 , 9 ]. A critical aspect of transporter function, associated to their transmembrane nature, is their continuous and dynamic interactions with membrane lipids, a challenge not faced by soluble proteins [ 10 ].…”

Identification and Analysis of Long Non-coding RNAs in Leuciscus waleckii Adapted to Highly Alkaline Conditions

“…Endocytosis plays an important role in regulating the renewal and abundance of ion channels. Cells can transfer ion channel proteins located on the membrane into the cells via endocytosis and then degrade them via the lysosomes or recycle them back to the plasma membrane (Estadella et al, 2020). The RUFY2-coding gene was correlated with LNC_033457 expression patterns and is known to interact with Etk and participate in the regulation of endocytosis (Yang et al, 2002).…”

Activation Mechanisms of the VPS34 Complexes

“…These endosomal compartments are sorted in a variety of ways, and their membranes undergo a variety of membrane trafficking and deformations, including tubulation, fission/scission, tethering, and fusion. These are vital for receptor and ion channel recycling, formation of multivesicular bodies (MBVs), and endosome maturation from early to late endosomes [252][253][254]. PtdIns(3)P is essential for the majority of these events.…”