Synaptic Zn 2 + and febrile seizure susceptibility

Hong

et al. 2020

IJMS

Zinc is a trace metal ion in the central nervous system that plays important biological roles, such as in catalysis, structure, and regulation. It contributes to antioxidant function and the proper functioning of the immune system. In view of these characteristics of zinc, it plays an important role in neurophysiology, which leads to cell growth and cell proliferation. However, after brain disease, excessively released and accumulated zinc ions cause neurotoxic damage to postsynaptic neurons. On the other hand, zinc deficiency induces degeneration and cognitive decline disorders, such as increased neuronal death and decreased learning and memory. Given the importance of balance in this context, zinc is a biological component that plays an important physiological role in the central nervous system, but a pathophysiological role in major neurological disorders. In this review, we focus on the multiple roles of zinc in the brain.

Section: Friendmentioning

confidence: 99%

Zinc in the Brain: Friend or Foe?

Hong

et al. 2020

IJMS

“…Similar ZnR/GPR39 responses were observed in postsynaptic neurons of the auditory brainstem nucleus, the dorsal cochlear nucleus [ 63 ]. Importantly, ZnR/GPR39 activity was shown to enhance neuronal inhibitory tone, and zinc deficiency is associated with epilepsy and seizures, suggesting the significant physiological role of ZnR/GPR39 [ 53 , 64 , 65 , 66 , 67 , 68 ]. Luminal application of Zn 2+ to colon epithelial cells, colonocytes, was sufficient to activate the plasma membrane ZnR/GPR39 [ 69 ], which is highly expressed in this tissue [ 70 , 71 ].…”

Section: Identification Of a Zn 2+ -Sensing Recmentioning

confidence: 99%

The Zinc Sensing Receptor, ZnR/GPR39, in Health and Disease

Hershfinkel

2018

IJMS

A distinct G-protein coupled receptor that senses changes in extracellular Zn2+, ZnR/GPR39, was found in cells from tissues in which Zn2+ plays a physiological role. Most prominently, ZnR/GPR39 activity was described in prostate cancer, skin keratinocytes, and colon epithelial cells, where zinc is essential for cell growth, wound closure, and barrier formation. ZnR/GPR39 activity was also described in neurons that are postsynaptic to vesicular Zn2+ release. Activation of ZnR/GPR39 triggers Gαq-dependent signaling and subsequent cellular pathways associated with cell growth and survival. Furthermore, ZnR/GPR39 was shown to regulate the activity of ion transport mechanisms that are essential for the physiological function of epithelial and neuronal cells. Thus, ZnR/GPR39 provides a unique target for therapeutically modifying the actions of zinc in a specific and selective manner.

“…Recently, studies have shown that human mutations that alter zinc affinity on NR2A-containing NMDA receptors are associated with childhood epilepsies and cognitive deficits [ 60 ]. Decreased Zn 2+ serum levels have also been linked to febrile seizures in both humans and animal models [ 61 ]. In the context that enhanced extracellular citrate is convulsive [ 51 ], it seems likely that reduced zinc levels through citrate chelation are a mechanism that could at least partially contribute to excitation–inhibition imbalance and seizure susceptibility.…”

Section: The Zinc Chelation Hypothesis: a Mechanism Linking High mentioning

confidence: 99%

“…Citrate chelation of free zinc reduces the availability of zinc for the NMDA receptor, relieving the negative allosteric effect of zinc on NMDA receptor function, thereby increasing calcium flux through the NMDA receptor (note larger arrow indicating enhanced flux of calcium through the NMDA receptor). Schematics in A and B were motivated from [ 30 , 61 ]; ( C ) kinetic model simulations [ 55 , 62 ] of NMDA receptor currents generated by a 5 s pulse of glutamate under normal conditions (i.e., with free zinc) and under conditions in which extracellular citrate has chelated free zinc (i.e., without free zinc). Citrate chelation induces a larger and more sustained NMDA receptor current; ( D ) response of the kinetic model to six synaptic-like 1-ms pulses of glutamate, simulating a burst of gluatmatergic synaptic activity.…”

Section: Figurementioning

confidence: 99%

Plasma Membrane Na+-Coupled Citrate Transporter (SLC13A5) and Neonatal Epileptic Encephalopathy

et al. 2017

SLC13A5 is a Na+-coupled transporter for citrate that is expressed in the plasma membrane of specific cell types in the liver, testis, and brain. It is an electrogenic transporter with a Na+:citrate3− stoichiometry of 4:1. In humans, the Michaelis constant for SLC13A5 to transport citrate is ~600 μM, which is physiologically relevant given that the normal concentration of citrate in plasma is in the range of 150–200 μM. Li+ stimulates the transport function of human SLC13A5 at concentrations that are in the therapeutic range in patients on lithium therapy. Human SLC13A5 differs from rodent Slc13a5 in two important aspects: the affinity of the human transporter for citrate is ~30-fold less than that of the rodent transporter, thus making human SLC13A5 a low-affinity/high-capacity transporter and the rodent Slc13a5 a high-affinity/low-capacity transporter. In the liver, SLC13A5 is expressed exclusively in the sinusoidal membrane of the hepatocytes, where it plays a role in the uptake of circulating citrate from the sinusoidal blood for metabolic use. In the testis, the transporter is expressed only in spermatozoa, which is also only in the mid piece where mitochondria are located; the likely function of the transporter in spermatozoa is to mediate the uptake of citrate present at high levels in the seminal fluid for subsequent metabolism in the sperm mitochondria to generate biological energy, thereby supporting sperm motility. In the brain, the transporter is expressed mostly in neurons. As astrocytes secrete citrate into extracellular medium, the potential function of SLC13A5 in neurons is to mediate the uptake of circulating citrate and astrocyte-released citrate for subsequent metabolism. Slc13a5-knockout mice have been generated; these mice do not have any overt phenotype but are resistant to experimentally induced metabolic syndrome. Recently however, loss-of-function mutations in human SLC13A5 have been found to cause severe epilepsy and encephalopathy early in life. Interestingly, there is no evidence of epilepsy or encephalopathy in Slc13a5-knockout mice, underlining the significant differences in clinical consequences of the loss of function of this transporter between humans and mice. The markedly different biochemical features of human SLC13A5 and mouse Slc13a5 likely contribute to these differences between humans and mice with regard to the metabolic consequences of the transporter deficiency. The exact molecular mechanisms by which the functional deficiency of the citrate transporter causes epilepsy and impairs neuronal development and function remain to be elucidated, but available literature implicate both dysfunction of GABA (γ-aminobutyrate) signaling and hyperfunction of NMDA (N-methyl-d-aspartate) receptor signaling. Plausible synaptic mechanisms linking loss-of-function mutations in SLC13A5 to epilepsy are discussed.