Hormone-induced secretory and nuclear translocation of calmodulin: Oscillations of calmodulin concentration with the nucleus as an integrator

Craske, Madeleine L.; Takeo, Teruko; Gerasimenko, Oleg Vsevolodovich; Vaillant, Camille; Török, Katalin; Petersen, O. H.; Tepikin, Alexei V.

doi:10.1073/pnas.96.8.4426

Cited by 81 publications

(64 citation statements)

References 54 publications

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“…CaM is an important intracellular Ca 2+ sensor, influencing many cellular events (21). CaM is a relatively small protein, which can be dialyzed into cells via a patch clamp pipette (whole-cell configuration) (20), and is therefore likely to be washed out of two-photon permeabilized cells. We tested the hypothesis that the difference between the modest effects of ethanol in intact cells and the substantial effects in two-photon permeabilized cells might be due to lack of CaM in the permeabilized preparation.…”

Section: Resultsmentioning

confidence: 99%

“…We tested the hypothesis that the difference between the modest effects of ethanol in intact cells and the substantial effects in two-photon permeabilized cells might be due to lack of CaM in the permeabilized preparation. In these experiments we used a CaM concentration of 2.5 μM, because this is the estimated normal cytoplasmic CaM level in pancreatic acinar cells (20). Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The effect of CaM could be due to inhibition of IP 3 R opening, which has been reported in some systems (39)(40)(41), although there is currently no agreement about the mechanism of action of CaM on IP 3 Rs (42). Irrespective of the mechanism of action, the protective effect of CaM on the granular store is of considerable interest, particularly in view of data showing that the physiological local Ca 2+ spikes in the granular region elicited by hormonal stimulation recruit CaM from the basolateral cytoplasm to the granular region (20). This recruitment of CaM occurring during physiological stimulation (20) may in view of our data be regarded as a functionally important process evolved to protect the granular region from excessive Ca 2+ liberation that could lead to the potentially dangerous intragranular trypsinogen activation (43,44) due to the ion exchange concept by Quesada and Verdugo (5,45).…”

Section: Discussionmentioning

confidence: 99%

“…Addition of the Ca 2+ sensor calmodulin (CaM) to the external solution-which had access to the intracellular (cytosolic) compartment through the hole in the plasma membrane created by two-photon laser lightmarkedly reduced the ability of ethanol to release Ca 2+ from intracellular stores and also markedly inhibited trypsinogen activation. A CaM concentration of 2.5 μM, which corresponds roughly to the normal intracellular CaM concentration in intact acinar cells (20), abolished the Ca 2+ -releasing effect of 10 mM ethanol as well as the trypsinogen activation and markedly reduced the effects of 100 mM ethanol. The effects of CaM in the permeabilized cells were abolished by addition of CaM inhibitor peptide and the relatively small effects of ethanol on intact acinar cells were virtually abolished by the CaM activator CALP-3.…”

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Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Gerasimenko

Lür

Ferdek

et al. 2011

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

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Alcohol abuse is a major global health problem, but there is still much uncertainty about the mechanisms of action. So far, the effects of ethanol on ion channels in the plasma membrane have received the most attention. We have now investigated actions on intracellular calcium channels in pancreatic acinar cells. Our aim was to discover the mechanism by which alcohol influences calcium homeostasis and thereby understand how alcohol can trigger premature intracellular trypsinogen activation, which is the initiating step for alcohol-induced pancreatitis. We used intact or twophoton permeabilized acinar cells isolated from wild-type mice or mice in which inositol trisphosphate receptors of type 2 or types 2 and 3 were knocked out. In permeabilized pancreatic acinar cells even a relatively low ethanol concentration elicited calcium release from intracellular stores and intracellular trypsinogen activation. The calcium sensor calmodulin (at a normal intracellular concentration) markedly reduced ethanol-induced calcium release and trypsinogen activation in permeabilized cells, effects prevented by the calmodulin inhibitor peptide. A calmodulin activator virtually abolished the modest ethanol effects in intact cells. Both ethanol-elicited calcium liberation and trypsinogen activation were significantly reduced in cells from type 2 inositol trisphosphate receptor knockout mice. More profound reductions were seen in cells from double inositol trisphosphate receptor (types 2 and 3) knockout mice. The inositol trisphosphate receptors, required for normal pancreatic stimulus-secretion coupling, are also responsible for the toxic ethanol action. Calmodulin protects by reducing calcium release sensitivity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 90%

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Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Gerasimenko

Lür

Ferdek

et al. 2011

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

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“…For short calcium spikes or low-frequency repetitive calcium spikes, no equalization occurs, and nuclear amplitudes of free Ca 2+ -CaM concentration remain small compared with those in the cytosol. It is likely that such differences in nuclear versus cytosolic free Ca 2+ -CaM signals exist in many cell types, as calcium-triggered nuclear accumulation of CaM has been observed in several previous studies [12][13][14][15].…”

Section: Differential Control Of Local Free Ca 2+ -Cam Concentration mentioning

confidence: 90%

Mobilization of late-endosomal cholesterol is inhibited by Rab guanine nucleotide dissociation inhibitor

et al. 2000

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Background: Many targets of calcium signaling pathways are activated or inhibited by binding the Ca 2+ -liganded form of calmodulin (Ca 2+ -CaM). Here, we test the hypothesis that local Ca 2+ -CaM-regulated signaling processes can be selectively activated by local intracellular differences in free Ca 2+ -CaM concentration.Results: Energy-transfer confocal microscopy of a fluorescent biosensor was used to measure the difference in the concentration of free Ca 2+ -CaM between nucleus and cytoplasm. Strikingly, short receptor-induced calcium spikes produced transient increases in free Ca 2+ -CaM concentration that were of markedly higher amplitude in the cytosol than in the nucleus. In contrast, prolonged increases in calcium led to equalization of the nuclear and cytosolic free Ca 2+ -CaM concentrations over a period of minutes. Photobleaching recovery and translocation measurements with fluorescently labeled CaM showed that equalization is likely to be the result of a diffusion-mediated net translocation of CaM into the nucleus. The driving force for equalization is a higher Ca 2+ -CaM-buffering capacity in the nucleus compared with the cytosol, as the direction of the free Ca 2+ -CaM concentration gradient and of CaM translocation could be reversed by expressing a Ca 2+ -CaM-binding protein at high concentration in the cytosol.Conclusions: Subcellular differences in the distribution of Ca 2+ -CaM-binding proteins can produce gradients of free Ca 2+ -CaM concentration that result in a net translocation of CaM. This provides a mechanism for dynamically regulating local free Ca 2+ -CaM concentrations, and thus the local activity of Ca 2+ -CaM targets. Free Ca 2+ -CaM signals in the nucleus remain low during brief or low-frequency calcium spikes, whereas high-frequency spikes or persistent increases in calcium cause translocation of CaM from the cytoplasm to the nucleus, resulting in similar concentrations of nuclear and cytosolic free Ca 2+ -CaM.

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Polarity in intracellular calcium signaling

1999

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The concentration of free calcium ions (Ca2+) in the cytosol is precisely regulated and can be rapidly increased in response to various types of stimuli. Since Ca2+ can be used to control different processes in the same cell, the spatial organization of cytosolic Ca2+ signals is of considerable importance. Polarized cells have advantages for Ca2+ studies since localized signals can be related to particular organelles. The pancreatic acinar cell is well‐characterized with a clearly polarized structure and function. Since the discovery of the intracellular Ca2+‐releasing function of inositol 1,4,5‐trisphosphate (IP3) in the pancreas in the early 1980s, this cell has become a popular study object and is now one of the best‐characterized with regard to Ca2+ signaling properties. Stimulation of pancreatic acinar cells with the neurotransmitter acetylcholine or the hormone cholecystokinin evokes Ca2+ signals that are either local or global, depending on the agonist concentration and the length of the stimulation period. The nature of the Ca2+ transport events across the basal and apical plasma membranes as well as the involvement of the endoplasmic reticulum (ER), the nucleus, the mitochondria, and the secretory granules in Ca2+ signal generation and termination have become much clearer in recent years. BioEssays 21:851–860, 1999. © 1999 John Wiley & Sons, Inc.

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Hormone-induced secretory and nuclear translocation of calmodulin: Oscillations of calmodulin concentration with the nucleus as an integrator

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Cited by 81 publications

References 54 publications

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Mobilization of late-endosomal cholesterol is inhibited by Rab guanine nucleotide dissociation inhibitor

Polarity in intracellular calcium signaling

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Hormone-induced secretory and nuclear translocation of calmodulin: Oscillations of calmodulin concentration with the nucleus as an integrator

Abstract: ABSTRACT

Cited by 81 publications

References 54 publications

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca 2+ release through IP 3 receptors

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca 2+ release through IP 3 receptors

Mobilization of late-endosomal cholesterol is inhibited by Rab guanine nucleotide dissociation inhibitor

Polarity in intracellular calcium signaling

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Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors