Deletion of TRPC3 in Mice Reduces Store-Operated Ca2+ Influx and the Severity of Acute Pancreatitis

Kim, Min Seuk; Hong, Jeong Hee; Li, Qin; Shin, Dong Min; Abramowitz, Joel; Birnbaumer, Lutz; Muallem, Shmuel

doi:10.1053/j.gastro.2009.07.042

Cited by 133 publications

(153 citation statements)

References 40 publications

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“…Our findings that blockade of intracellular Ca 2ϩ reduced calcineurin activation are in general agreement with previous reports that sustained Ca 2ϩ signals are required to activate calcineurin (22,23 (12,25,46), Ca 2ϩ store depletion, and the subsequent opening of store operated Ca 2ϩ entry (SOCE) channels (47)(48)(49).…”

Section: Discussionsupporting

confidence: 82%

Bile Acids Induce Pancreatic Acinar Cell Injury and Pancreatitis by Activating Calcineurin

Muili

Wang

Orabi

et al. 2013

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 82%

Bile Acids Induce Pancreatic Acinar Cell Injury and Pancreatitis by Activating Calcineurin

Muili

Wang

Orabi

et al. 2013

Journal of Biological Chemistry

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“…Alternatively, the production of DAG may be insufficient to activate TRPC3 and PKC in immature B cells, since it has been reported that an increase of intracellular Ca 2+ and hydrolysis of PtdIns(4,5)P 2 are induced in response to BCR cross-linking in mature B cells but an increase of intracellular Ca 2+ levels is induced in the relative absence of PtdIns(4,5)P 2 hydrolysis in immature B cells (King and Monroe, 2000). These aspects can be addressed using TRPC3 knockout mice, in which B-cell function has not been demonstrated yet (Hartmann et al, 2008;Kim et al, 2009). Interestingly, our preliminary results demonstrated that application of the TRPC3-selective inhibitor Pyr3 (Kiyonaka et al, 2009) suppressed BCR-induced Ca 2+ responses, sustained PKC PM translocation, and ERK activation in murine primary splenic B cells (T.N., unpublished data).…”

Section: +mentioning

confidence: 87%

Ca2+ influx and protein scaffolding via TRPC3 sustain PKCβ and ERK activation in B cells

Numaga

Nishida

Kiyonaka

et al. 2010

Journal of Cell Science

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Summary Ca2+ signaling mediated by phospholipase C that produces inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3 ] and diacylglycerol (DAG) controls lymphocyte activation. In contrast to store-operated Ca 2+ entry activated by Ins(1,4,5)P 3 -induced Ca 2+ release from endoplasmic reticulum, the importance of DAG-activated Ca 2+ entry remains elusive. Here, we describe the physiological role of DAG-activated Ca 2+ entry channels in B-cell receptor (BCR) signaling. In avian DT40 B cells, deficiency of transient receptor potential TRPC3 at the plasma membrane (PM) impaired DAG-activated cation currents and, upon BCR stimulation, the sustained translocation to the PM of protein kinase C (PKC) that activated extracellular signal-regulated kinase (ERK). Notably, TRPC3 showed direct association with PKC that maintained localization of PKC at the PM. Thus, TRPC3 functions as both a Ca 2+ -permeable channel and a protein scaffold at the PM for downstream PKC activation in B cells.

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“…During the last 20 years, the family of TRPC (canonical transient receptor potential) channels has been proposed as candidates for SOCE. Number of reports has shown a reduced SOCE activity when TRPC expression was knocked down or knocked out [8][9][10][11]. When exogenously expressed some TRPC channels displayed SOCE activity [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Thapsigargin activates Ca2+ entry both by store-dependent, STIM1/Orai1-mediated, and store-independent, TRPC3/PLC/PKC-mediated pathways in human endothelial cells

et al. 2011

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a b s t r a c tThe ER Ca 2+ sensor STIM1 and the Ca 2+ channel Orai1 are key players in store-operated Ca 2+ entry (SOCE). In addition, channels from the TRPC family were also shown to be engaged during SOCE, while their precise implication remains controversial. In this study, we investigated the molecular players involved in SOCE triggered by the SERCA pump inhibitor thapsigargin in an endothelial cell line, the EA.hy926. siRNA directed against STIM1 or Orai1 reduced Ca 2+ entry by about 50-60%, showing that a large part of the entry is independent from these proteins. Blocking the PLC or the PKC pathway completely abolished thapsigargin-induced Ca 2+ entry in cells depleted from STIM1 and/or Orai1. The phorbol ester PMA or the DAG analog OAG restored the Ca 2+ entry inhibited by PLC blockers, showing an involvement of PLC/PKC pathway in SOCE. Using pharmacological inhibitors or siRNA revealed that the PKCeta is required for Ca 2+ entry, and pharmacological inhibition of the tyrosine kinase Src also reduced Ca 2+ entry. TRPC3 silencing diminished the entry by 45%, while the double STIM1/TRPC3 invalidation reduced Ca 2+ entry by more than 85%. Hence, in EA.hy926 cells, TG-induced Ca 2+ entry results from the activation of the STIM1/Orai1 machinery, and from the activation of TRPC3.

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Deletion of TRPC3 in Mice Reduces Store-Operated Ca2+ Influx and the Severity of Acute Pancreatitis

Cited by 133 publications

References 40 publications

Bile Acids Induce Pancreatic Acinar Cell Injury and Pancreatitis by Activating Calcineurin

Bile Acids Induce Pancreatic Acinar Cell Injury and Pancreatitis by Activating Calcineurin

Ca2+ influx and protein scaffolding via TRPC3 sustain PKCβ and ERK activation in B cells

Thapsigargin activates Ca2+ entry both by store-dependent, STIM1/Orai1-mediated, and store-independent, TRPC3/PLC/PKC-mediated pathways in human endothelial cells

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