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, 113 (2), 313-28

TRP Channels of Intracellular Membranes


TRP Channels of Intracellular Membranes

Xian-Ping Dong et al. J Neurochem.


Ion channels are classically understood to regulate the flux of ions across the plasma membrane in response to a variety of environmental and intracellular cues. Ion channels serve a number of functions in intracellular membranes as well. These channels may be temporarily localized to intracellular membranes as a function of their biosynthetic or secretory pathways, i.e., en route to their destination location. Intracellular membrane ion channels may also be located in the endocytic pathways, either being recycled back to the plasma membrane or targeted to the lysosome for degradation. Several channels do participate in intracellular signal transduction; the most well known example is the inositol 1,4,5-trisphosphate receptor (IP(3)R) in the endoplasmic reticulum. Some organellar intracellular membrane channels are required for the ionic homeostasis of their residing organelles. Several newly-discovered intracellular membrane Ca(2+) channels actually play active roles in membrane trafficking. Transient receptor potential (TRP) proteins are a superfamily (28 members in mammal) of Ca(2+)-permeable channels with diverse tissue distribution, subcellular localization, and physiological functions. Almost all mammalian TRP channels studied thus far, like their ancestor yeast TRP channel (TRPY1) that localizes to the vacuole compartment, are also (in addition to their plasma membrane localization) found to be localized to intracellular membranes. Accumulated evidence suggests that intracellularly-localized TRP channels actively participate in regulating membrane traffic, signal transduction, and vesicular ion homeostasis. This review aims to provide a summary of these recent works. The discussion will also be extended to the basic membrane and electrical properties of the TRP-residing compartments.


Figure 1
Figure 1. Intracellular location and putative activation mechanisms of TRP channels
TRPs can be divided into 6 groups (TRPC, TRPV, TRPM, TRPA, TRPML, and TRPP). TRPML1–3, TRPV2, and TRPY1 (yeast TRP yvc1), and TRPM7 (in red) are likely to play active roles in membrane traffic and exocytosis. TRPM2, TRPM8, TRPV1, TRPP1, TRPA1, and TRPV4 (in green) have been shown to be active in intracellular membranes and may play roles in intracellular signal transduction. TRPC3–6, TRPMV5/6, TRPM1, TRPM7, and TRPML2/3 (in blue) have been shown to undergo regulated exocytosis. Intracellular localization of other TRPs (in black) has not been well documented.
Figure 2
Figure 2. Intracellular TRP channels in the secretory and endocytic pathways
Intracellular compartments undergo membrane fusion and fission/budding. There are two kinds of membrane fusions: “kiss and run” and complete fusion. In some steps, transport vesicles fission off from the source membranes and fuse with the target membranes to delivery cargos. Ca2+-sensitive membrane fusion and fission steps are indicated with white arrows. The molecular identities of intracellular compartments are defined by specific recruitment of small G proteins (Rab and Arf GTPases) and the composition of phosphoinositides (PIPs). The luminal ionic (H+ and Ca2+) composition is indicated for each organelle. (A) The Biosynthetic Pathway essentially all TRPs (labeled in mixed color) in the biosynthetic pathway may be present in the ER (pH 7.2; [Ca2+]ER ~ 0. 7 mM; PI(4)P + PI(4,5)P2) and the Golgi apparatus (Trans Golgi Network; TGN; pH 6.4; [Ca2+]Golgi ~ 0. 3–0.7 mM; PI(4)P + PI(4,5)P2). The Ca2+ gradients are established by the thapsigargin (TG) -sensitive SERCA (Sarco/Endoplasmic Reticulum Ca2+) pump in the ER, and by both SERCA and TG-insensitive SPCA (Secretory Pathway Ca2+) pumps in the Golgi. TRPV1 is reportedly functional in the ER or Golgi. There are intermediate transport vesicles derived from the ER and the Golgi apparatus. These transport vesicles may deliver cargos to early endosomes (EE; pH 6.0; [Ca2+]EE ~ 0. 003–2 mM; PI(3)P; Rab5), late endosomes (LE; pH 5.5; [Ca2+]LE ~ 0.5 mM; PI(3)P+PI(3,5)P2; Rab7 and Rab9), or the plasma membrane (PM) through secretory vesicles (SV; pH6.4)) and/or secretory granules (SG; pH 6.4). [Ca2+]EE changes significantly during the maturation of early EE, dropping from 2 mM in the primary endocytic vesicles to ~ 0.003 mM 20 min after endocytosis (Gerasimenko et al. 1998). SVs and SGs deliver the newly synthesized TRP channels to the PM. (B) The Endocytic Pathway EEs are derived from the primary endocytic vesicles after endocytosis. In addition to the late endocytic pathway, contents in the EE can also be sorted into recycling endosomes (RE; pH 6.4; [Ca2+]RE ~ 0. 003 – 2 mM; PI(3)P + PI(4)P + PI(4,5)P2; Rab11/Rab4), which are subsequently recycled back to the PM. TRP channels may be detected in the EE and RE as cargos during this cycle of endocytosis and recycling. In addition, TRPV2, TRPML2, and TRPML3 may play active roles in the early endocytic pathways. TRPV2 is activated by low pH and a reduction of intra-endosomal [Cl]. The channel activity of TRPML2 (in RE) may regulate the activation of small GTPase Arf6, an important regulator of the recycling pathway. The activation mechanism of TRPML3 (in EE) is still not known. In sympathetic neurons, TRPM7 is localized in synaptic vesicles (SyV; pH 6.4) that are derived from EEs. The channel activity of TRPM7 plays a role in controlling neurotransmitter release. In EEs, intra-endosomal Ca2+ release may activate Ca2+ sensor proteins such as Synaptotagmin (Syt) and calmodulin (CaM). Subsequently, homotypic and heterotypic fusion events occur. In the late endocytic pathways, late endosomes (LEs) may “kiss and run” or completely fuse with other LE or lysosomes (LY; pH 4.5; [Ca2+]LY ~ 0.5 mM; PI(3)P+PI(3,5)P2; Rab7). TRPML1–3 channels are predominantly localized in LEs and LYs. Activation of TRPML channels by unidentified cellular cues may induce intralysosomal Ca2+ release. LEs, LYs, or hybrids of LEs and LYs, will then undergo calmodulin- (CaM) or synaptotagmin- (Syt) dependent membrane fusion or fission/budding. Membrane proteins enter the degradation pathway following membrane invagination to form multi-vesicular bodies (MVB) in LEs. The inward budding of internal vesicles into MVBs is a Ca2+-dependent process. In addition, MVBs may also undergo Ca2+-dependent exocytosis to release internal vesicles (exosomes) (Savina et al. 2003). Retrograde (retromer) transport vesicles (TVs), derived from EEs, LEs, or LYs upon membrane fission, transport lipids and proteins retrogradely to the TGN. In addition to fusion with LEs, LYs can also undergo fusion with autophagosomes (APs) to form autolysosomes (ALs), or with the PM, i.e., lysosomal exocytosis. TRPM2 in LEL compartments is activated by ADPR, and likely by NAADP as well.
Figure 3
Figure 3. Electrical properties of lysosomes
While the ionic compositions of extracellular space and cytosol have been well established, ion concentrations in the lumen of lysosome are not clear. The luminal pH is between 4 and 5 and is established by a V-type ATPase. The [Ca2+]LY is ~ 0.5 mM, which is maintained by an unidentified H+-Ca2+ exchanger. The resting membrane potential (Δφ cytosol relative to lumen or extracellular) of the cell is ~ −70 mV (cytoplasmic-side negative). Based on studies on synaptic vesicles and phagosomes, the membrane potential across the lysosomal membrane is estimated to be ~ + 30 to + 110 mV (luminal-side positive).

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