Editors' ChoiceCalcium signaling

Does a Leaky Store Lead to a Long Life?

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Science Signaling  10 Mar 2009:
Vol. 2, Issue 61, pp. ec90
DOI: 10.1126/scisignal.261ec90

Ca2+ released from intracellular stores can contribute to cell death by apoptosis. Transient receptor potential (TRP) channels conduct calcium, leading Wegierski et al. to investigate the role in apoptosis of TRPP2 channels found in the endoplasmic reticulum (ER). When TRPP2 channels were heterologously expressed in Xenopus oocytes, they could not be detected in the plasma membrane; rather, they appeared to localize to the ER because the oocytes showed a decrease in the amplitude of Cl currents activated by Ca2+ release from the ER. When TRPP2 channels were expressed in transfected human embryonic kidney (HEK) 293 cells, immunofluorescence analysis indicated that they localized to the ER, and Ca2+ imaging of these cells showed a smaller Ca2+ signal after stimulation of purinergic G protein–coupled receptors (reflecting Ca2+ release from the ER). Moreover, experiments with the calcium ionophore ionomycin in HEK293 cells, and the ER calcium pump inhibitor thapsigargin in HeLa cells stably expressing TRPP2, indicated that TRPP2 decreased ER Ca2+ content. Indeed, experiments with an ER-targeted Ca2+ sensor indicated that [Ca2+]ER was decreased in HeLa cells expressing TRPP2. Consistent with this, the increase in mitochondrial [Ca2+] after stimulation of Ca2+ release from the ER was diminished. In contrast, TRPP2 knockdown [in Madin Darby canine kidney (MDCK) cells] led to increased Ca2+ signals in response to ATP or ionomycin. The effects of TRPP2 on ER Ca2+ content appeared to result from an increase in the passive ER Ca2+ leak rather than decreased accumulation. TRPP2 knockdown sensitized MDCK cells to ceramide-induced apoptosis, an effect that the authors postulate may be pertinent to the enhanced apoptosis associated with autosomal dominant polycystic kidney disease, a genetic disorder that can result from TRPP2 mutation.

T. Wegierski, D. Steffl, C. Kopp, R. Tauber, B. Buchholz, R. Nitschke, E. W. Kuehn, G. Walz, M. Köttgen, TRPP2 channels regulate apoptosis through the Ca2+ concentration in the endoplasmic reticulum. EMBO J. 28, 490–499 (2009). [PubMed]

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