An NAADP-gated Two-pore Channel Targeted to the Plasma Membrane Uncouples Triggering from Amplifying Ca2+ Signals

Brǎiloiu, Eugen; Rahman, Taufiq; Churamani, Dev; Prole, David L.; Brailoiu, G. Cristina; Hooper, Robert; Taylor, Colin W.; Patel, Sandip

doi:10.1074/jbc.m110.162073

Cited by 159 publications

(279 citation statements)

References 37 publications

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“…6), provide firm evidence that TRPML1 is not a target for NAADP and support TPCs as NAADP-activated channels. Indeed, our conclusions are consistent with three recent studies reporting channel activity for TPC2 from isolated lysosomes, immunopurified TPC2 fused into lipid bilayers, or in cells expressing plasma membrane targeted TPC2 (42,49,50). Importantly, in two of these studies, currents were eliminated or modified by mutations in the putative channel pore (42,50).…”

Section: Discussionsupporting

confidence: 82%

“…However, it is possible that the TPCs are not targeted to the plasma membrane even when overexpressed, thereby explaining the lack of affect on TRPML activity. The N terminus of TPC2 contains a lysosomal targeting di-leucine motif (42). In a recent study, we showed that N-terminally truncated TPC2 (TPC2delN) is targeted to the plasma membrane.…”

Section: Resultsmentioning

confidence: 99%

“…C-terminally GFP-tagged TPC2 lacking amino acids 3-25 (TPC2delN) was described in Ref. 42. pCS2ϩ constructs encoding for C-terminally Myc-tagged TPC1 and TPC2 were generated by replacing the GFP tag of the corresponding C-terminally GFP-tagged constructs with five Myc tags.…”

Section: Methodsmentioning

confidence: 99%

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Transient Receptor Potential Mucolipin 1 (TRPML1) and Two-pore Channels Are Functionally Independent Organellar Ion Channels

Yamaguchi

Jha

et al. 2011

Journal of Biological Chemistry

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104

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NAADP is a potent second messenger that mobilizes Ca 2؉from acidic organelles such as endosomes and lysosomes. The molecular basis for Ca 2؉ release by NAADP, however, is uncertain. TRP mucolipins (TRPMLs) and two-pore channels (TPCs) are Ca 2؉ -permeable ion channels present within the endolysosomal system. Both have been proposed as targets for NAADP. In the present study, we probed possible physical and functional association of these ion channels. Exogenously expressed TRPML1 showed near complete colocalization with TPC2 and partial colocalization with TPC1. TRPML3 overlap with TPC2 was more modest. TRPML1 and to some extent TRPML3 co-immunoprecipitated with TPC2 but less so with TPC1. Current recording, however, showed that TPC1 and TPC2 did not affect the activity of wild-type TRPML1 or constitutively active TRPML1(V432P). N-terminally truncated TPC2 (TPC2delN), which is targeted to the plasma membrane, also failed to affect TRPML1 and TRPML1 ( ؊/؊ cells. We conclude that although TRPML1 and TPCs are present in the same complex, they function as two independent organellar ion channels and that TPCs, not TRPMLs, are the targets for NAADP. Ca2ϩ plays a major role in the function of intracellular organelles including biosynthesis and membrane trafficking (1, 2). Although the mechanism controlling Ca 2ϩ in the endoplasmic reticulum has been studied extensively, very little is known about Ca 2ϩ homeostasis by other organelles. Furthermore, although accumulating evidence indicates that acidic organelles such as endosomes and lysosomes are dynamic Ca 2ϩ stores, the molecular basis for Ca 2ϩ release from these so-called "acidic Ca 2ϩ stores" (3) is at present defined poorly. By far, the best characterized route for mobilization of acidic Ca 2ϩ stores is through the production of the potent Ca 2ϩ -releasing second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP) 5 (4). The Ca 2ϩ -mobilizing properties of NAADP were discovered in sea urchin eggs (5), in which NAADP was shown to mobilize Ca 2ϩ not from the endoplasmic reticulum but instead from lysosome-related organelles (6). Its effects have subsequently been extended to a variety of cell types, including pancreatic acinar and ␤ cells, smooth muscle cells, neurons, and breast cancer cells (4). NAADP is produced by several extracellular stimuli in an agonist-specific manner and implicated in a number of physiological responses, including fertilization, glucose sensing, exocytosis, and neuronal growth (4). Deregulated lysosomal Ca 2ϩ signaling may also result in disease (2,7,8). Despite the physiological and potential pathophysiological importance of NAADP signaling, the molecular identity of the NAADP receptor is not entirely clear (9). Recently, members of the transient receptor potential mucolipin (TRPML) (10, 11) and two-pore channel (TPC) (12-16) families, which are all present in the endo/lysosomal system, have been proposed as candidates.TRPMLs form a subfamily of the superfamily of the TRP channels. The founding member is TRPML1, which was ide...

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Section: Discussionsupporting

confidence: 82%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Transient Receptor Potential Mucolipin 1 (TRPML1) and Two-pore Channels Are Functionally Independent Organellar Ion Channels

Yamaguchi

Jha

et al. 2011

Journal of Biological Chemistry

Self Cite

104

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“…A mutant of TPC2 lacking a di-leucine motif in its N-terminal has recently been shown to be localized to the PM instead of the lysosomal membrane, suggesting that this motif is required for its localization to acidic organelles. 28 Plant TPC family members including OsTPC1 possess a similar motif in their N-terminal tail, which is consistent with the localization to the VM. The PM localization of OsTPC1 in cultured rice cells 15,20 suggests some differences in sorting machinery of the TPC family membrane proteins among plant species.…”

Section: Intracellular Localization and Physiological Function Of A Rsupporting

confidence: 78%

Intracellular localization and physiological function of a rice Ca²⁺-permeable channel OsTPC1

Kurusu

Hamada

Koyano

et al. 2012

Plant Signaling & Behavior

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Despite the molecular diversity of signaling components among plants and animals, Ca 2+ has been established as a common second messenger in most eukaryotic cells. 1,2 Though electrophysiological studies have revealed several types of Ca 2+ -permeable channels localized at the plasma membrane (PM) and vacuolar membrane (VM) in many plant species, 3 their molecular identity are still largely unknown. Homologs of the major voltage-dependent Ca 2+ channels (VDCCs) are not found in plants. 3 In turn, the two-pore channel (TPC) family, originally isolated from rat, 4 is homologous to a half structure of the α1-subunit of vertebrate VDCCs. 5 Human TPCs mediate nicotinic acid adenine dinucleotide phosphate-induced Ca 2+ release from acidic organelles in HEK293 cells. 6 Arabidopsis AtTPC1 shows a slow-activating vacuolar cation channel activity 7,8 and be involved in the sucrose-induced Ca 2+ rise, 9 abscisic acid-induced repression of germination 10 and the stomatal response to extracellular Ca 2+ changes. 7,10 Tobacco NtTPC1s have roles in increasing Ca 2+ concentrations, defense-related gene expression, and regulation of hypersensitive cell death triggered by cryptogein, an elicitor from an oomycete, in tobacco BY-2 cells. 11 Rice and wheat TPC1s appear to function in responses to abiotic stresses. 12,13 Role of OsTPC1 in Xylanase Elicitor-Triggered Defense Responses in RiceCharacterization of the retrotransposon-insertional knockout mutant of rice Ostpc1 revealed that OsTPC1 affected the

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“…54,60,61 N-Linked glycosylation is the process whereby carbohydrate residues are added to asparagine residues of proteins, specifically a subset residing in the Asn-X-Ser/Thr motif (where X is any residue except proline), that can affect many key biological processes including cell adhesion, molecular trafficking and clearance, receptor activation, signal transduction, and endocytosis. 62 Both TPC1 and TPC2 are N-glycosylated conforming to the consensus Asn-X-Ser/Thr at residues 599, 611, and TPC1 has an additional glycosylation site at residue 616.…”

Section: Structurementioning

confidence: 99%

Two-pore channels (TPCs): Novel voltage-gated ion channels with pleiotropic functions

Feijóo‐Bandín¹,

García-Vence²,

García-Rúa³

et al. 2016

Channels

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Two-pore channels (TPC1-3) comprise a subfamily of the eukaryotic voltage-gated ion channels (VGICs) superfamily that are mainly expressed in acidic stores in plants and animals. TPCS are widespread across the animal kingdom, with primates, mice and rats lacking TPC3, and mainly act as Ca C and Na C channels, although it was also suggested that they could be permeable to other ions. Nowadays, TPCs have been related to the development of different diseases, including Parkinsons disease, obesity or myocardial ischemia. Due to this, their study has raised the interest of the scientific community to try to understand their mechanism of action in order to be able to develop an efficient drug that could regulate TPCs activity. In this review, we will provide an updated view regarding TPCs structure, function and activation, as well as their role in different pathophysiological processes.

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An NAADP-gated Two-pore Channel Targeted to the Plasma Membrane Uncouples Triggering from Amplifying Ca2+ Signals

Cited by 159 publications

References 37 publications

Transient Receptor Potential Mucolipin 1 (TRPML1) and Two-pore Channels Are Functionally Independent Organellar Ion Channels

Transient Receptor Potential Mucolipin 1 (TRPML1) and Two-pore Channels Are Functionally Independent Organellar Ion Channels

Intracellular localization and physiological function of a rice Ca²⁺-permeable channel OsTPC1

Two-pore channels (TPCs): Novel voltage-gated ion channels with pleiotropic functions

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An NAADP-gated Two-pore Channel Targeted to the Plasma Membrane Uncouples Triggering from Amplifying Ca2+ Signals

Cited by 159 publications

References 37 publications

Transient Receptor Potential Mucolipin 1 (TRPML1) and Two-pore Channels Are Functionally Independent Organellar Ion Channels

Transient Receptor Potential Mucolipin 1 (TRPML1) and Two-pore Channels Are Functionally Independent Organellar Ion Channels

Intracellular localization and physiological function of a rice Ca2+-permeable channel OsTPC1

Two-pore channels (TPCs): Novel voltage-gated ion channels with pleiotropic functions

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Intracellular localization and physiological function of a rice Ca²⁺-permeable channel OsTPC1