scholarly journals Ecm29-mediated proteasomal distribution modulates excitatory GABA responses in the developing brain

2020 ◽  
Vol 219 (2) ◽  
Author(s):  
Min Lee ◽  
Yen-Chen Liu ◽  
Chen Chen ◽  
Chi-Huan Lu ◽  
Shao-Tzu Lu ◽  
...  

Neuronal GABAergic responses switch from excitatory to inhibitory at an early postnatal period in rodents. The timing of this switch is controlled by intracellular Cl− concentrations, but factors determining local levels of cation-chloride cotransporters remain elusive. Here, we report that local abundance of the chloride importer NKCC1 and timely emergence of GABAergic inhibition are modulated by proteasome distribution, which is mediated through interactions of proteasomes with the adaptor Ecm29 and the axon initial segment (AIS) scaffold protein ankyrin G. Mechanistically, both the Ecm29 N-terminal domain and an intact AIS structure are required for transport and tethering of proteasomes in the AIS region. In mice, Ecm29 knockout (KO) in neurons increases the density of NKCC1 protein in the AIS region, a change that positively correlates with a delay in the GABAergic response switch. Phenotypically, Ecm29 KO mice showed increased firing frequency of action potentials at early postnatal ages and were hypersusceptible to chemically induced convulsive seizures. Finally, Ecm29 KO neurons exhibited accelerated AIS developmental positioning, reflecting a perturbed AIS morphological plastic response to hyperexcitability arising from proteasome inhibition, a phenotype rescued by ectopic Ecm29 expression or NKCC1 inhibition. Together, our findings support the idea that neuronal maturation requires regulation of proteasomal distribution controlled by Ecm29.

1998 ◽  
Vol 79 (4) ◽  
pp. 1746-1754 ◽  
Author(s):  
Andreas Scholz ◽  
Noboru Kuboyama ◽  
Gunter Hempelmann ◽  
Werner Vogel

Scholz, Andreas, Noboru Kuboyama, Gunter Hempelmann, and Werner Vogel. Complex blockade of TTX-resistant Na+ currents by lidocaine and bupivacaine reduce firing frequency in DRG neurons. J. Neurophysiol. 79: 1746–1754, 1998. Mechanisms of blockade of tetrodotoxin-resistant (TTXr) Na+ channels by local anesthetics in comparison with the sensitivity of tetrodotoxin-sensitive (TTXs) Na+ channels were studied by means of the patch-clamp technique in neurons of dorsal root ganglions (DRG) of rat. Half-maximum inhibitory concentration (IC50) for the tonic block of TTXr Na+ currents by lidocaine was 210 μmol/l, whereas TTXs Na+ currents showed five times lower IC50 of 42 μmol/l. Bupivacaine blocked TTXr and TTXs Na+ currents more potently with IC50 of 32 and 13 μmol/l, respectively. In the inactivated state, TTXr Na+ channel block by lidocaine showed higher sensitivities (IC50 = 60 μmol/l) than in the resting state underlying tonic blockade. The time constant τ1 of recovery of TTXr Na+ channels from inactivation at −80 mV was slowed from 2 to 5 ms after addition of 10 μmol/l bupivacaine, whereas the τ2 value of ∼500 ms remained unchanged. The use-dependent block of TTXr Na+ channels led to a progressive reduction of current amplitudes with increasing frequency of stimulation, which was ≤53% block at 20 Hz in 10 μmol/l bupivacaine and 81% in 100 μmol lidocaine. The functional importance of the use-dependent block was confirmed in current-clamp experiments where 30 μmol/l of lidocaine or bupivacaine did not suppress the single action potential but clearly reduced the firing frequency of action potentials again with stronger potency of bupivacaine. Because it was found that TTXr Na+ channels predominantly occur in smaller sensory neurons, their blockade might underlie the suppression of the sensation of pain. Different sensitivities and varying proportions of TTXr and TTXs Na+ channels could explain the known differential block in spinal anesthesia. We suggest that the frequency reduction at low local anesthetic concentrations may explain the phenomenon of paresthesia where sensory information are suppressed gradually during spinal anesthesia.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lorenzo Ferlini ◽  
Fuhong Su ◽  
Jacques Creteur ◽  
Fabio Silvio Taccone ◽  
Nicolas Gaspard

AbstractThe increase in neuronal activity induced by a single seizure is supported by a rise in the cerebral blood flow and tissue oxygenation, a mechanism called neurovascular coupling (NVC). Whether cerebral and systemic hemodynamics are able to match neuronal activity during recurring seizures is unclear, as data from rodent models are at odds with human studies. In order to clarify this issue, we used an invasive brain and systemic monitoring to study the effects of chemically induced non-convulsive seizures in sheep. Despite an increase in neuronal activity as seizures repeat (Spearman’s ρ coefficient 0.31, P < 0.001), ictal variations of cerebral blood flow remained stable while it progressively increased in the inter-ictal intervals (ρ = 0.06, P = 0.44 and ρ = 0.22; P = 0.008). We also observed a progressive reduction in the inter-ictal brain tissue oxygenation (ρ =  − 0.18; P = 0.04), suggesting that NVC was unable to compensate for the metabolic demand of these closely repeating seizures. At the systemic level, there was a progressive reduction in blood pressure and a progressive rise in cardiac output (ρ =  − 0.22; P = 0.01 and ρ = 0.22; P = 0.01, respectively), suggesting seizure-induced autonomic dysfunction.


Author(s):  
D.C. Hixson ◽  
J.C. Chan ◽  
J.M. Bowen ◽  
E.F. Walborg

Several years ago Karasaki (1) reported the production of type C virus particles by Novikoff ascites hepatocarcinoma cells. More recently, Weinstein (2) has reported the presence of type C virus particles in cell cultures derived from transplantable and primary hepatocellular carcinomas. To date, the biological function of these virus and their significance in chemically induced hepatocarcinogenesis are unknown. The present studies were initiated to determine a possible role for type C virus particles in chemically induced hepatocarcinogenesis. This communication describes results of studies on the biological and surface properties of type C virus associated with Novikoff hepatocarcinoma cells.Ecotropic and xenotropic murine leukemia virus (MuLV) activity in ascitic fluid of Novikoff tumor-bearing rats was assayed in murine sarcoma virus transformed S+L- mouse cells and S+L- mink cells, respectively. The presence of sarcoma virus activity was assayed in non-virus-producing normal rat kidney (NRK) cells. Ferritin conjugates of concanavalin A (Fer-Con wheat germ agglutinin (Fer-WGA), and Ricinus communis agglutinins I and II (Fer-RCAI and Fer-RCAII) were used to probe the structure and topography of saccharide determinants present on the viral envelope.


2014 ◽  
Vol 52 (01) ◽  
Author(s):  
HM Zimmermann ◽  
N Moro ◽  
R Sonntag ◽  
JM Bangen ◽  
YA Nevzorova ◽  
...  

2015 ◽  
Vol 53 (12) ◽  
Author(s):  
N Gehrke ◽  
MA Wörns ◽  
Y Alt ◽  
A Waisman ◽  
N Hoevelmeyer ◽  
...  

Planta Medica ◽  
2016 ◽  
Vol 81 (S 01) ◽  
pp. S1-S381
Author(s):  
J Hussein ◽  
DA Elmatty ◽  
D Medhat ◽  
NM Mesbah ◽  
AR Farrag ◽  
...  
Keyword(s):  
Omega 3 ◽  

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