Importance of Zinc in the Central Nervous System: The Zinc-Containing Neuron

Frederickson, Christopher J.; Suh, Sang Won; Schwartz, David A.; Frederickson, C.J.; Thompson, Richard B.

doi:10.1093/jn/130.5.1471s

Cited by 755 publications

(560 citation statements)

References 90 publications

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“…MF terminals co‐release Zn 2+ from their massive boutons during glutamatergic neurotransmission (Frederickson et al . 2000) where it acts via postsynaptic metabotropic Zn 2+ receptors (mZnRs) on CA3 pyramidal neurons (Chorin et al . 2011).…”

Section: Gpcr Modulation: a Brief Overviewmentioning

confidence: 99%

Regulation of neuronal chloride homeostasis by neuromodulators

Mahadevan

Woodin

2016

The Journal of Physiology

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KCC2 is the central regulator of neuronal Cl− homeostasis, and is critical for enabling strong hyperpolarizing synaptic inhibition in the mature brain. KCC2 hypofunction results in decreased inhibition and increased network hyperexcitability that underlies numerous disease states including epilepsy, neuropathic pain and neuropsychiatric disorders. The current holy grail of KCC2 biology is to identify how we can rescue KCC2 hypofunction in order to restore physiological levels of synaptic inhibition and neuronal network activity. It is becoming increasingly clear that diverse cellular signals regulate KCC2 surface expression and function including neurotransmitters and neuromodulators. In the present review we explore the existing evidence that G‐protein‐coupled receptor (GPCR) signalling can regulate KCC2 activity in numerous regions of the nervous system including the hypothalamus, hippocampus and spinal cord. We present key evidence from the literature suggesting that GPCR signalling is a conserved mechanism for regulating chloride homeostasis. This evidence includes: (1) the activation of group 1 metabotropic glutamate receptors and metabotropic Zn2+ receptors strengthens GABAergic inhibition in CA3 pyramidal neurons through a regulation of KCC2; (2) activation of the 5‐hydroxytryptamine type 2A serotonin receptors upregulates KCC2 cell surface expression and function, restores endogenous inhibition in motoneurons, and reduces spasticity in rats; and (3) activation of A3A‐type adenosine receptors rescues KCC2 dysfunction and reverses allodynia in a model of neuropathic pain. We propose that GPCR‐signals are novel endogenous Cl− extrusion enhancers that may regulate KCC2 function.

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Section: Gpcr Modulation: a Brief Overviewmentioning

confidence: 99%

Regulation of neuronal chloride homeostasis by neuromodulators

Mahadevan

Woodin

2016

The Journal of Physiology

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“…We choose the autometallographic (AMG) and the N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) fluorescence method, as it shows both the terminal and the translocated zinc ions (Danscher, 1996;Frederickson and Danscher, 1990;Frederickson et al, 1987Frederickson et al, , 2000Suh et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Neurotoxic Zinc Translocation into Hippocampal Neurons is Inhibited by Hypothermia and is Aggravated by Hyperthermia after Traumatic Brain Injury in Rats

Suh

Frederickson

Danscher

2005

J Cereb Blood Flow Metab

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Hypothermia reduces excitotoxic neuronal damage after seizures, cerebral ischemia and traumatic brain injury (TBI), while hyperthermia exacerbates damage from these insults. Presynaptic release of ionic zinc (Zn 2 þ ), translocation and accumulation of Zn 2 þ ions in postsynaptic neurons are important mechanisms of excitotoxic neuronal injury. We hypothesized that temperature-dependent modulation of excitotoxicity is mediated in part by temperature-dependent changes in the synaptic release and translocation of Zn 2 þ . In the present studies, we used autometallographic (AMG) and fluorescent imaging of N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) staining to quantify the influence of temperature on translocation of Zn 2 þ into hippocampal neurons in adult rats after weight drop-induced TBI. The central finding was that TBI-induced Zn 2 þ translocation is strongly influenced by brain temperature. Vesicular Zn 2 þ release was detected by AMG staining 1 h after TBI. At 301C, hippocampus showed almost no evidence of vesicular Zn 2 þ release from presynaptic terminals; at 36.51C, the hippocampus showed around 20% to 30% presynaptic vesicular Zn 2 þ release; and at 391C vesicular Zn 2 þ release was significantly greater (40% to 60%) than at 36.51C. At 6 h after TBI, intracellular Zn 2 þ accumulation was detected by the TSQ staining method, which showed that Zn 2 þ translocation also paralleled the vesicular Zn 2 þ release. Neuronal injury, assessed by counting eosinophilic neurons, also paralleled the translocation of Zn 2 þ , being minimal at 301C and maximal at 391C. We conclude that pathological Zn 2 þ translocation in brain after TBI is temperature-dependent and that hypothermic neuronal protection might be mediated in part by reduced Zn 2 þ translocation.

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“…9,12,[15][16][17][18][19][20] The most common action of clinically used antidepressants on nAChRs appears to be a noncompetitive inhibitory process, 9,12,[15][16][17][18][19][20] and it is probable that this action contributes to improving depressed mood states. 21 On the other hand, zinc is contained in neurons that are widely distributed throughout the nervous system; 22 and it is released from GABAergic and glutamatergic nerve endings, 23,24 reaching an extracellular concentration of B300 mM. 25 This cation modulates synaptic transmission by interacting with pre-and postsynaptic membrane proteins, such as receptors and ion channels.…”

Section: Introductionmentioning

confidence: 99%

Combined actions of zinc and fluoxetine on nicotinic acetylcholine receptors

2004

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Zinc and nicotinic acetylcholine receptors (nAChRs) seem to be associated with major depression, and some antidepressants, including fluoxetine (Prozac), antagonize nAChRs. Therefore, a study was made of the modulation of neuronal a4b4 and muscle a1b1gd nAChRs, expressing in oocytes, by the combined action of zinc and fluoxetine. At a holding potential of -60 mV, 200 mM zinc increased by 361% the currents elicited by acetylcholine (ACh currents) for a4b4 and by 182% for a1b1gd nAChRs. In contrast, 5 mM fluoxetine reduced the ACh currents to 31% for a4b4 and to 45% for a1b1gd nAChRs. Additionally, fluoxetine reduced more the ACh currents in the presence of zinc: to 17% for a4b4 and to 19% for a1b1gd nAChRs, and after washing out the fluoxetine the ACh current did not recover its zinc-potentiated value. Moreover, when ACh-activated nAChRs were exposed first to fluoxetine and then zinc was added, the potentiating effect of zinc was very small for muscle nAChRs and was nil for neuronal receptors. Thus, the inhibiting effect of fluoxetine prevails over the potentiating action of zinc. Finally, the effects of both zinc and fluoxetine were voltage independent, indicating that these substances interact outside the ion channel. As fluoxetine nullifies the effects of zinc, it appears that both substances interact in the same site. These results should help understand better the roles played by zinc, antidepressants, nAChRs and their combination in brain functions and in the treatment of depression.

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Importance of Zinc in the Central Nervous System: The Zinc-Containing Neuron

Cited by 755 publications

References 90 publications

Regulation of neuronal chloride homeostasis by neuromodulators

Regulation of neuronal chloride homeostasis by neuromodulators

Neurotoxic Zinc Translocation into Hippocampal Neurons is Inhibited by Hypothermia and is Aggravated by Hyperthermia after Traumatic Brain Injury in Rats

Combined actions of zinc and fluoxetine on nicotinic acetylcholine receptors

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