A tool coming of age: thapsigargin as an inhibitor of sarco-endoplasmic reticulum Ca2+-ATPases

Treiman, Marek; Caspersen, Casper; Christensen, Søren Brøgger

doi:10.1016/s0165-6147(98)01184-5

Cited by 554 publications

(422 citation statements)

References 45 publications

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“…The i.c.v. administration of thapsigargin, a compound which selectively inhibits Ca 2C uptake into the endoplasmic reticulum by inhibiting the sarco-endoplasmic reticulum ATPases (SERCAs) and thus increasing the intracellular Ca 2C concentration (Treiman et al, 1998), increased the mouse immobility time evidencing the induction of a depressant-like effect. These observations suggest that a supraspinal increase in intracellular calcium contents is involved in the modulation of mood leading to a depressant-like effect in laboratory animals further complementing and extending studies performed on peripheral blood cells from depressed subjects indicating that patients with affective disorders have an enhanced intracellular Ca 2C response (Emamghoreishi et al, 1997;Yamawaki et al, 1998;Manji and Lenox, 2000).…”

Section: Discussionmentioning

confidence: 99%

Blockade of intracellular calcium release induces an antidepressant-like effect in the mouse forced swimming test

2006

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The role of intracellular calcium in the modulation of a depressant-like condition was investigated in the mouse forced swimming test. I.c.v. administration of TMB-8 (0.23e46.3 nmol per mouse), a blocker of Ca 2C release from intracellular stores, decreased the mouse immobility time. I.c.v. injection of thapsigargin (0.003e3 nmol per mouse), compound which selectively inhibits Ca 2C uptake into the endoplasmic reticulum, produced, 60 min after administration, a depressant-like condition. Xestospongin C (1e100 pmol per mouse i.c.v.), an InsP 3 -receptor antagonist, decreased the mouse immobility time. By contrast, D-myo-inositol (5.4e540 pmol per mouse i.c.v.), compound which produces InsP 3 , resulted in a depressant-like effect. Similarly, ryanodine (0.1e600 pmol per mouse i.c.v.), an RyR antagonist, decreased the immobility time values whereas the administration of 4-chloro-m-cresol (0.1e100 pmol per mouse i.c.v.), an RyR agonist, showed an opposite effect. The antidepressant-like effects observed with TMB-8, xestospongin C and ryanodine were comparable to that produced by the antidepressant drugs amitriptyline and clomipramine. The treatments employed did not produce any behavioural impairment of mice as revealed by the rota-rod and hole board tests indicating that the antidepressant-and depressant-like effects were not due to a compromised locomotor activity and spontaneous motility of the treated animals. These results indicate that a central variation in intracellular calcium contents is involved in the modulation of a depressive-like condition in the mouse forced swimming test. In particular, the blockade of both InsP 3 Rs and RyRs appears to play an important role in the induction of an antidepressant-like effect, whereas the stimulation of these receptors is involved in a depressant-like response of mice.

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Section: Discussionmentioning

confidence: 99%

Blockade of intracellular calcium release induces an antidepressant-like effect in the mouse forced swimming test

2006

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“…Because the caffeine-ryanodine-sensitive store is involved in CICR (Kuba, 1994), we next sought to examine the possibility that native BDNF release evoked by patterned electrical stimulation involves CICR. One of several criteria to establish the involvement of CICR is the presence of a caffeinesensitive intracellular calcium store that is modulated by inhibitors of sarcoplasmic-endoplasmic reticulum Ca 2ϩ -ATPase, such as thapsigargin (Treiman et al, 1998). Therefore, we next examined the effect of blocking CICR with thapsigargin and dantrolene on release of native BDNF from hippocampal neurons in response to patterned electrical stimulation.…”

Section: Electrical Stimulation-evoked Release Of Native Bdnf From Himentioning

confidence: 99%

Cellular Mechanisms Regulating Activity-Dependent Release of Native Brain-Derived Neurotrophic Factor from Hippocampal Neurons

2002

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Brain-derived neurotrophic factor (BDNF) plays a critical role in activity-dependent modifications of neuronal connectivity and synaptic strength, including establishment of hippocampal long-term potentiation (LTP). To shed light on mechanisms underlying BDNF-dependent synaptic plasticity, the present study was undertaken to characterize release of native BDNF from newborn rat hippocampal neurons in response to physiologically relevant patterns of electrical field stimulation in culture, including tonic stimulation at 5 Hz, bursting stimulation at 25 and 100 Hz, and theta-burst stimulation (TBS). Release was measured using the ELISA in situ technique, developed in our laboratory to quantify secretion of native BDNF without the need to first overexpress the protein to nonphysiological levels. Each stimulation protocol resulted in a significant increase in BDNF release that was tetrodotoxin sensitive and occurred in the absence of glutamate receptor activation. However, 100 Hz tetanus and TBS, stimulus patterns that are most effective in inducing hippocampal LTP, were significantly more effective in releasing native BDNF than lower-frequency stimulation. For all stimulation protocols tested, removal of extracellular calcium, or blockade of N-type calcium channels, prevented BDNF release. Similarly, depletion of intracellular calcium stores with thapsigargin and treatment with dantrolene, an inhibitor of calcium release from caffeine-ryanodine-sensitive stores, markedly inhibited activity-dependent BDNF release. Our results indicate that BDNF release can encode temporal features of hippocampal neuronal activity. The dual requirement for calcium influx through N-type calcium channels and calcium mobilization from intracellular stores strongly implicates a role for calcium-induced calcium release in activity-dependent BDNF secretion.

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“…Cadmium also did not block the en¯urane-induced mIPSC frequency increase ( Figures 5A, 6). Thapsigargin (1 ± 5 mM), which depletes calcium from intracellular stores by blocking its uptake (Treiman et al, 1998), increased the variability in the response to en¯urane so that the increase was no longer signi®cant ( Figures 5B, 6). The compound KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiorea), which selectively blocks the Na-Ca exchanger operating in the reverse direction (Iwamoto & Shigekawa, 1998;Shigekawa & Iwamoto, 2001) did not block en¯urane-induced increases in mIPSC frequency ( Figures 5C, 6).…”

Section: Mechanism Of Enflurane-induced Mipsc Frequency Increasementioning

confidence: 99%

Pre‐ and postsynaptic volatile anaesthetic actions on glycinergic transmission to spinal cord motor neurons

Gong

Kendig

2002

British J Pharmacology

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1 A common anaesthetic endpoint, prevention of withdrawal from a noxious stimulus, is determined primarily in spinal cord, where glycine is an important inhibitory transmitter. To de®ne pre-and postsynaptic anaesthetic actions at glycinergic snyapses, the e ects of volatile anaesthetic agents on spontaneous and evoked glycinergic currents in spinal cord motor neurons from 6 ± 14-day old rats was investigated. 2 The volatile anaesthetic agents en¯urane, iso¯urane and halothane signi®cantly increased the frequency of glycinergic mIPSCs, en¯urane to 190.4% of control+22.0 (mean+s.e.m., n=7, P50.01), iso¯urane to 199.0%+28.8 (n=7, P50.05) and halothane to 198.2%+19.5 (n=7, P50.01). However without TTX, iso¯urane and halothane had no signi®cant e ect and en¯urane decreased sIPSC frequency to 42.5% of control+12.4 (n=6, P50.01). All the anaesthetics prolonged the decay time constant (t) of both spontaneous and glycine-evoked currents without increasing amplitude. With TTX total charge transfer was increased; without TTX charge transfer was unchanged (iso¯urane and halothane) or decreased (en¯urane). 3 En¯urane-induced mIPSC frequency increases were not signi®cantly a ected by Cd 2+ (50 mM), thapsigargin (1 ± 5 mM), or KB-R7943 (5 mM). KB-R7943 and thapsigargin together abolished the en¯urane-induced increase in mIPSC frequency. 4 There are opposing facilitatory and inhibitory actions of volatile anaesthetics on glycine release dependent on calcium homeostatic mechanisms and sodium channels respectively. Under normal conditions (no TTX) the absolute amount of glycinergic inhibition does not increase. The contribution of glycinergic inhibition to anaesthesia may depend on its duration rather than its absolute magnitude.

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A tool coming of age: thapsigargin as an inhibitor of sarco-endoplasmic reticulum Ca2+-ATPases

Cited by 554 publications

References 45 publications

Blockade of intracellular calcium release induces an antidepressant-like effect in the mouse forced swimming test

Blockade of intracellular calcium release induces an antidepressant-like effect in the mouse forced swimming test

Cellular Mechanisms Regulating Activity-Dependent Release of Native Brain-Derived Neurotrophic Factor from Hippocampal Neurons

Pre‐ and postsynaptic volatile anaesthetic actions on glycinergic transmission to spinal cord motor neurons

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