Two-pore Channels (TPC2s) and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) at Lysosomal-Sarcoplasmic Reticular Junctions Contribute to Acute and Chronic β-Adrenoceptor Signaling in the Heart

Capel, Rebecca A.; Bolton, Emma L.; Lin, Wee Khang; Aston, Daniel; Wang, Yanwen; Liu, Wei; Wang, Xin; Burton, Rebecca A.B.; Bloor-Young, Duncan; Shade, Kai-Ting C.; Ruas, Margarida; Parrington, John; Churchill, Grant C.; Lei, Ming; Galione, Antony; Terrar, Derek A.

doi:10.1074/jbc.m115.684076

Cited by 70 publications

(152 citation statements)

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“…Indeed, expression of both isoforms, but particularly of TPC2, was much more pronounced in the embryo than in the adult. Recent studies of TPC knockout mice have shown them to have abnormalities in smooth muscle contraction (Tugba Durlu-Kandilci et al, 2010), receptor trafficking and endolysosomal function , storage and utilization of cholesterol by the liver (Grimm et al, 2014), angiogenesis (Favia et al, 2014), skeletal muscle function (Cang et al, 2013, brown adipose tissue thermogenesis (Lear et al, 2014) and heart contraction in response to b-adrenergic stimulation (Capel et al, 2015). Although these abnormalities may reflect defects in the signalling pathways regulating physiological responses in the affected tissues, it is also possible that they are due to disturbances of TPC expression during development.…”

Section: Role Of Naadp and Tpcs During Fertilization And Embryogenesismentioning

confidence: 99%

Calcium signals regulated by NAADP and two-pore channels - their role in development, differentiation and cancer

Parrington¹,

Lear²,

Hachem³

2015

Int. J. Dev. Biol.

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Section: Role Of Naadp and Tpcs During Fertilization And Embryogenesismentioning

confidence: 99%

Calcium signals regulated by NAADP and two-pore channels - their role in development, differentiation and cancer

Parrington¹,

Lear²,

Hachem³

2015

Int. J. Dev. Biol.

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“…Their functions have been shown to be involved in various physiological processes, such as endocytosis and endosomal trafficking (5, 6), lysosomal morphology and pigmentation (7,8), autophagy (9, 10), and nutrient metabolism via the mammalian target of rapamycin (mTOR) complex (11). Not surprisingly, given their central physiological role, defects in TPC channels are associated with a variety of disabling human disorders (9,(12)(13)(14)(15)(16)(17).Despite their physiological importance, some biophysical properties of mammalian TPC channels are still under debate (18). Mammalian TPC channels were initially identified as receptors of nicotinic acid adenine dinucleotide phosphate (NAADP), a Ca 2+ -mobilizing second messenger, and responsible for Ca 2+ release from the acidic organelles (19)(20)(21).…”

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confidence: 99%

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confidence: 99%

Tuning the ion selectivity of two-pore channels

Guo

Zeng

Jiang

2017

Proc. Natl. Acad. Sci. U.S.A.

111

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Organellar two-pore channels (TPCs) contain two copies of a Shakerlike six-transmembrane (6-TM) domain in each subunit and are ubiquitously expressed in plants and animals. Interestingly, plant and animal TPCs share high sequence similarity in the filter region, yet exhibit drastically different ion selectivity. Plant TPC1 functions as a nonselective cation channel on the vacuole membrane, whereas mammalian TPC channels have been shown to be endo/lysosomal Na + -selective or Ca 2+ -release channels. In this study, we performed systematic characterization of the ion selectivity of TPC1 from Arabidopsis thaliana (AtTPC1) and compared its selectivity with the selectivity of human TPC2 (HsTPC2). We demonstrate that AtTPC1 is selective for Ca 2+ over Na Our results also confirm that HsTPC2 is a Na + -selective channel activated by phosphatidylinositol 3,5-bisphosphate. Guided by our recent structure of AtTPC1, we converted AtTPC1 to a Na + -selective channel by mimicking the selectivity filter of HsTPC2 and identified key residues in the TPC filters that differentiate the selectivity between AtTPC1 and HsTPC2. Furthermore, the structure of the Na + -selective AtTPC1 mutant elucidates the structural basis for Na + selectivity in mammalian TPCs.two-pore channel | ion selectivity | crystal structure T wo-pore channels (TPCs) are organellar cation channels ubiquitously expressed in animals and plants (1, 2) and belong to the voltage-gated ion channel superfamily (3). TPC channels contain two homologous Shaker-like six-transmembrane (6-TM) domains in each subunit and function as homodimers. They are believed to be evolutionary intermediates between homotetrameric voltage-gated potassium channels and the four-domain, single-subunit, voltage-gated sodium/calcium channels (4).In human and animals, TPC channels (TPC1 and TPC2) are localized to the endo/lysosomal membranes and regulate the ionic homeostasis within these acidic organelles. Their functions have been shown to be involved in various physiological processes, such as endocytosis and endosomal trafficking (5, 6), lysosomal morphology and pigmentation (7,8), autophagy (9, 10), and nutrient metabolism via the mammalian target of rapamycin (mTOR) complex (11). Not surprisingly, given their central physiological role, defects in TPC channels are associated with a variety of disabling human disorders (9,(12)(13)(14)(15)(16)(17).Despite their physiological importance, some biophysical properties of mammalian TPC channels are still under debate (18). Mammalian TPC channels were initially identified as receptors of nicotinic acid adenine dinucleotide phosphate (NAADP), a Ca 2+ -mobilizing second messenger, and responsible for Ca 2+ release from the acidic organelles (19)(20)(21). Although the NAADP-dependent endo/lysosomal Ca 2+ release is attributed directly to the Ca 2+ conduction of TPC channels activated by NAADP in some studies (16,(22)(23)(24)(25)(26), several recent studies demonstrate that TPCs are Na + -selective channels that are activated by phosphatidylinositol 3...

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“…Previous studies regarding CaMKII in the nervous system and heart have resulted in its functions being well characterized [38-40]. Accumulated evidence has shown that CaMKII activation is closely related to increased intracellular calcium levels [8, 9].…”

Section: Discussionmentioning

confidence: 99%

Periodic Mechanical Stress INDUCES Chondrocyte Proliferation and Matrix Synthesis via CaMKII-Mediated Pyk2 Signaling

Liang

Zeng

Wang

et al. 2017

Cell Physiol Biochem

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Background/Aims: Periodic mechanical stress can promote chondrocyte proliferation and matrix synthesis to improve the quality of tissue-engineered cartilage. Although the integrin β1–ERK1/2 signal cascade has been implicated in periodic mechanical stress-induced mitogenic effects in chondrocytes, the precise mechanisms have not been fully established. The current study was designed to probe the roles of CaMKII and Pyk2 signaling in periodic mechanical stress-mediated chondrocyte proliferation and matrix synthesis. Methods: Chondrocytes were subjected to periodic mechanical stress, proliferation was assessed by direct cell counting and CCK-8 assay; gene expressions were analyzed using quantitative real-time PCR, protein abundance by Western blotting. Results: Mechanical stress, markedly enhanced the phosphorylation levels of Pyk2 at Tyr⁴⁰² and CaMKII at Thr²⁸⁶. Both suppression of Pyk2 with Pyk2 inhibitor PF431396 or Pyk2 shRNA and suppression of CaMKII with CaMKII inhibitor KN-93 or CaMKII shRNA blocked periodic mechanical stress-induced chondrocyte proliferation and matrix synthesis. Additionally, either pretreatment with KN-93 or shRNA targeted to CaMKII prevented the activation of ERK1/2 and Pyk2 under conditions of periodic mechanical stress. Interestingly, in relation to periodic mechanical stress, in the context of Pyk2 inhibition with PF431396 or its targeted shRNA, only the phosphorylation levels of ERK1/2 were abrogated, while CaMKII signal activation was not affected. Moreover, the phosphorylation levels of CaMKII- Thr²⁸⁶ and Pyk2- Tyr⁴⁰² were abolished after pretreatment with blocking antibody against integrinβ1 exposed to periodic mechanical stress. Conclusion: Our results collectively indicate that periodic mechanical stress promotes chondrocyte proliferation and matrix synthesis through the integrinβ1–CaMKII–Pyk2–ERK1/2 signaling cascade.

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Two-pore Channels (TPC2s) and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) at Lysosomal-Sarcoplasmic Reticular Junctions Contribute to Acute and Chronic β-Adrenoceptor Signaling in the Heart

Cited by 70 publications

References 62 publications

Calcium signals regulated by NAADP and two-pore channels - their role in development, differentiation and cancer

Calcium signals regulated by NAADP and two-pore channels - their role in development, differentiation and cancer

Tuning the ion selectivity of two-pore channels

Periodic Mechanical Stress INDUCES Chondrocyte Proliferation and Matrix Synthesis via CaMKII-Mediated Pyk2 Signaling

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