CADMIUM RAPIDLY AND IRREVERSIBLY BLOCKS PRESYNAPTIC PHOSPHOLIPASE C-LINKED METABOTROPIC GLUTAMATE RECEPTORS

doi:10.1016/0197-0186(96)00008-3

Neurochemistry International

Volume 29, Issue 4, October 1996, Pages 371-381

https://doi.org/10.1016/0197-0186(96)00008-3 Get rights and content

Abstract

Calcium ions (Cd²⁺) inhibit inositol phosphate (IP) formation elicited by glutamate (GLU) or K⁺ ions, without affecting carbachol (Carb)-induced IP response in 8-day-old rat forebrain synaptoneurosomes and synaptosomes. On the contrary, Cd²⁺ was almost ineffective in blocking GLU- and K⁺-responses in hippocampal neurones in culture. The mechanism of Cd²⁺ inhibition was thus examined in synaptoneurosomes. Extensive washing of synaptoneurosomes pretreated for 1, 5, 15, or 30 min by 100 μM Cd²⁺ did not modify the inhibitory effect of Cd²⁺ on GLU-, K⁺- and A23187-evoked IP formation or its lack of effect on Carb response. The later addition of a high affinity Cd²⁺ chelator (100 μM), N, N, N′, N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) also did not reverse the inhibitory effect. TPEN, however, penetrates into synaptoneurosomes and efficiently displaces Cd²⁺ from the Fura-2—Cd²⁺ complex as shown by Fura-2 fluorescence recordings. TPEN is not easily removed from the intracellular space, as demonstrated by its ability to still block Cd²⁺-induced Fura-2 fluorescence increase after extensive washing. Pretreatment of synaptoneurosomes by this chelator did not prevent Cd²⁺ inhibition of GLU-induced IP formation. These data indicate that Cd²⁺ ions rapidly, irreversibly and extracellularly inhibit GLU-elicited IP formation in synaptoneurosomes or synaptosomes, but not in hippocampal neurones in culture. It is speculated that Cd²⁺ ions could allow one to distinguish the activity of presynaptic metabotropic glutamate receptors (mGLURs) linked to phosphoinositide metabolism from that of mGLURs located postsynaptically. Copyright © 1996 Elsevier Science Ltd.

Section snippets

Materials

Myo[2- ³H] inositol (15 Ci/mmol; 0.55 TBq/mmol) was purchased from Isotopchim (France). TPEN and Fura2-AM were from Interchim (Montluçon, France). All other chemicals were from Sigma, France.

Synaptoneurosome preparation

Synaptoneurosomes were prepared according to Hollingsworth et al. (1985), with modifications (Recasens et al., 1988). Briefly, 8-day-old Long-Evans rats were killed by decapitation and the forebrains quickly dissected and homogenized with a glass-glass dounce homogenizer, in 9 vols of Krebs-Ringer buffer

Effects of 5 min pretreatment of rat forebrain synaptoneurosomes with various Cd²⁺ concentrations on GLU-, K⁺-, A23187- and Carb-elicited IP accumulation

Pretreatment of synaptoneurosomes for 5 min with Cd²⁺ ions at 30, 100 and 300 μM, followed by two washings, produced a dose-dependent inhibition of GLU-, K⁺ and A23187-induced IP1 and IP2 formations (Fig. 1). Interestingly, only the highest Cd²⁺ concentration used (300 μM) inhibited by 43 and 39% Carb-stimulated IP1 and IP2 responses, respectively. Cd²⁺ (100 μM) inhibited 85, 60 and 43% of GLU-, K⁺- and A23187-induced IP1 accumulations, respectively; Carb response was not affected by this

DISCUSSION

Our data indicate that 100 μM Cd²⁺ ions potently, rapidly and irreversibly inhibit GLU-induced IP formation in rat forebrain synaptoneurosomes, without affecting muscarinic agonist-elicited IP responses. Cd²⁺ ions interact extracellularly and not intracellularly. These ions also affect K⁺- and A23187-stimulated IP production. This Cd²⁺ inhibitory effect also holds true in synaptosomes, but not in hippocampal neurones in culture.

Previous experiments from our laboratory have revealed that Cd²⁺

Acknowledgements

The authors are deeply grateful to Messrs M. Gallego and I. Sassetti for technical assistance. Dr J. Guiramand is supported by CNRS. This work was granted by the European Economic Community (BMH1-CT93-1033).

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From the data Biagioli et al. (2008) concluded that Cd2+ induced SERCA pump inhibition promotes an acute transient elevation of [Ca2+]cyt, whereas prolonged exposure to Cd2+ will result in depletion of ER Ca2+ pools and diminish the response to agonist-evoked Ca2+ signaling. In addition, reports in fibroblasts, lymphocytes and neuronal cells have demonstrated that Cd2+ may inhibit Ca2+-sensitive phospholipase C activity, as evidenced by a reduction of agonist-induced inositol phosphate formation (Muldoon et al., 1988; Grazia Cifone et al., 1989; Vignes et al., 1996). This could also contribute to the reduction of agonist-evoked Ca2+ signals in cells treated with Cd2+ for longer periods of time.
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^*: Part of the work reported in this original communication was presented at the symposium entitled Excitatory Amino Acid Signalling, which was held in Kyoto, Japan, 15–18 July 1995 (organised by Y. Yoneda and M. Toru). Dr Yoneda also acted as executive editor in the processing of this manuscript.

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COMMENTARYCADMIUM RAPIDLY AND IRREVERSIBLY BLOCKS PRESYNAPTIC PHOSPHOLIPASE C-LINKED METABOTROPIC GLUTAMATE RECEPTORS *

Abstract

Section snippets

Materials

Synaptoneurosome preparation

Effects of 5 min pretreatment of rat forebrain synaptoneurosomes with various Cd2+ concentrations on GLU-, K+-, A23187- and Carb-elicited IP accumulation

DISCUSSION

Acknowledgements

J. Biol. Chem.

Cell

J. Biol. Chem.

Neuron

Neurosci. Lett.

Eur. J. Pharmacol. Molec. Pharmacol.

Neurosci. Lett.

J. Biol. Chem.

Neuron

Int. J. Devel. Neurosci.

Brain Res.

Neuroscience

Neuron

Neurochem. Int.

Trends Biochem. Sci.

J. Biol. Chem.

J. Biol. Chem.

Trends Pharmacol. Sci.

Enhanced sensitivity of “metabotropic” glutamate receptors after induction of long-term potentiation in rat hippocampus

J. Neurochem.

Induction of LTP in the hippocampus needs synaptic activation of glutamate metabotropic receptors

Nature

Differential expression of phospholipase C specific for inositol phospholipids at the cell surface of rat glial cells and REF52 rat embryo fibroblasts

J. Neurochem.

Rapid accumulation of inositol phosphates in isolated rat superior cervical sympathetic ganglia exposed to V1-vasopressin and muscarinic cholinergic stimuli

Biochem J.

A molecular switch activated by metabotropic glutamate receptors regulates induction of long-term potentiation

Nature

COMMENTARY
CADMIUM RAPIDLY AND IRREVERSIBLY BLOCKS PRESYNAPTIC PHOSPHOLIPASE C-LINKED METABOTROPIC GLUTAMATE RECEPTORS *

Effects of 5 min pretreatment of rat forebrain synaptoneurosomes with various Cd²⁺ concentrations on GLU-, K⁺-, A23187- and Carb-elicited IP accumulation