Abstract
Two-pore channels (TPCs) constitute a small family of ion channels within membranes of intracellular acidic compartments, such as endosomes and lysosomes. They were shown to provide transient and locally restricted Ca2+-currents, likely responsible for fusion and/or fission events of endolysosomal membranes and thereby for intracellular vesicle trafficking. Genetic deletion of TPCs not only affects endocytosis, recycling, and degradation of various surface receptors but also uptake and impact of bacterial protein toxins and entry and intracellular processing of some types of viruses. This review points to important examples of these trafficking defects on one part but mainly focuses on the resulting impact of the TPC inactivation on receptor expression and receptor signaling. Thus, a detailed RNA sequencing analysis using TPC1-deficient fibroblasts uncovered a multitude of changes in the expression levels of surface receptors and their pathway-related signaling proteins. We refer to several classes of receptors such as EGF, TGF, and insulin as well as proteins involved in endocytosis.
Highlights
This basic structure is well known from numerous classes of ion channels, and it is thought that Two-pore channels (TPCs) form evolutionary intermediates between one-domain TRP and four-domain voltage gated Na+ or Ca2+ channels
TPC1/2 double knockouts showed numerous examples of co-localization of Rab5- and EGF-positive vesicles, whereas wildtype and TPC1-deficient MEF cells exhibited only minor co-localization. These observations suggest that epidermal growth factor receptor (EGFR) trafficking is more delayed in TPC2 knockout cells, which may be caused by a longer retention time of EGFR in late endolysosomal vesicles
Based on the data presented by Müller and colleagues, who described a close link between loss of TPC1 and gene expression changes in the EGFR pathway, we decided to have a closer look at pathways characterized by an ongoing signaling of internalized receptors, i.e., activated receptors present in “signaling endosomes”
Summary
Two-pore channels (TPCs) constitute a small family of cation channels within the membranes of endolysosomal organelles. Only two TPCs were identified, whereas several other species express three or even more functional tpc-genes. The name “two-pore channel” suggests an ion channel structure with two separate pores, but, the channel protein consists of two subunits forming a homodimer. Each subunit comprises two homologous domains, and each domain consists of six transmembrane segments. This basic structure is well known from numerous classes of ion channels, and it is thought that TPCs form evolutionary intermediates between one-domain TRP and four-domain voltage gated Na+ or Ca2+ channels. X-ray crystallography [4,5] Later, this was followed by the 3D structures of mouse TPC1 and human TPC2 using electron cryo-microscopy [6,7]. Functional studies in combination with these structural data indicate that the first four transmembrane segments of each domain participate in voltage sensing, while the fifth and the sixth segments constitute the pore region [6,7]
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