Contribution of Ion Channels to Neuropathologies

Editorial

13 March 2023

Editorial: Contribution of ion channels to neuropathologies

Miklos Kecskes

Steve Peigneur

and

Katharina Held

1,841 views

3 citations

Editors

Katharina Held

Heidelberg University Hospital

Balázs István Tóth

Faculty of Medicine, University of Debrecen

Medical College of Wisconsin

Impact

Original Research

10 January 2023

Functionally active TRPA1 ion channel is downregulated in peptidergic neurons of the Edinger-Westphal nucleus upon acute alcohol exposure

Ammar Al-Omari

, 7 more and

Viktória Kormos

Introduction: The centrally projecting Edinger-Westphal nucleus (EWcp) contributes to the control of alcohol consumption by its urocortin 1 (UCN1) and cocaine- and amphetamine-regulated transcript (CART) co-expressing peptidergic neurons. Our group recently showed that the urocortinergic centrally projecting EWcp is the primary seat of central nervous system transient receptor potential ankyrin 1 (TRPA1) cation channel mRNA expression. Here, we hypothesized that alcohol and its metabolites, that pass through the blood-brain barrier, may influence the function of urocortinergic cells in centrally projecting EWcp by activating TRPA1 ion channels. We aimed to examine the functional activity of TRPA1 in centrally projecting EWcp and its possible role in a mouse model of acute alcohol exposure.

Methods: Electrophysiological measurements were performed on acute brain slices of C57BL/6J male mice containing the centrally projecting EWcp to prove the functional activity of TRPA1 using a selective, potent, covalent agonist JT010. Male TRPA1 knockout (KO) and wildtype (WT) mice were compared with each other in the morphological studies upon acute alcohol treatment. In both genotypes, half of the animals was treated intraperitoneally with 1 g/kg 6% ethanol vs. physiological saline-injected controls. Transcardial perfusion was performed 2 h after the treatment. In the centrally projecting EWcp area, FOS immunohistochemistry was performed to assess neuronal activation. TRPA1, CART, and urocortin 1 mRNA expression as well as urocortin 1 and CART peptide content was semi-quantified by RNAscope in situ hybridization combined with immunofluorescence.

Results: JT010 activated TRPA1 channels of the urocortinergic cells in acute brain slices. Alcohol treatment resulted in a significant FOS activation in both genotypes. Alcohol decreased the Trpa1 mRNA expression in WT mice. The assessment of urocortin 1 peptide immunoreactivity revealed lower basal urocortin 1 in KO mice compared to WTs. The urocortin 1 peptide content was affected genotype-dependently by alcohol: the peptide content decreased in WTs while it increased in KO mice. Alcohol exposure influenced neither CART and urocortin 1 mRNA expression nor the centrally projecting EWcp/CART peptide content.

Conclusion: We proved the presence of functional TRPA1 receptors on urocortin 1 neurons of the centrally projecting EWcp. Decreased Trpa1 mRNA expression upon acute alcohol treatment, associated with reduced neuronal urocortin 1 peptide content suggesting that this cation channel may contribute to the regulation of the urocortin 1 release.

3,125 views

11 citations

Graphical conclusion. (A) Activated microglia contribute to the increased neuronal excitability, where the NTCCs are presynaptically upregulated, causing a Ca2+ misbalance influx and an excessive neurotransmitters release (like glutamate and Substance P) in the synaptic cleft, which is propagated postsynaptically, due to the NMDAR excessive activation. (B) Processes/conditions resulting from the altered signaling have been demonstrated in (A), where the overlapped zones represent similarities between the different neurological diseases: Migraine, Huntington’s disease, and Multiple Sclerosis.

Review

19 December 2022

Targeting N-type calcium channels in young-onset of some neurological diseases

Flavia Tasmin Techera Antunes

, 5 more and

Marcus Vinícius Gomez

4,402 views

6 citations

Original Research

29 September 2020

An SCN1B Variant Affects Both Cardiac-Type (NaV1.5) and Brain-Type (NaV1.1) Sodium Currents and Contributes to Complex Concomitant Brain and Cardiac Disorders

Rebecca Martinez-Moreno

, 8 more and

Ramon Brugada

Voltage-gated sodium (Na_V) channels are transmembrane proteins that initiate and propagate neuronal and cardiac action potentials. Na_V channel β subunits have been widely studied due to their modulatory role. Mice null for Scn1b, which encodes Na_V β1 and β1b subunits, have defects in neuronal development and excitability, spontaneous generalized seizures, cardiac arrhythmias, and early mortality. A mutation in exon 3 of SCN1B, c.308A>T leading to β1_p.D103V and β1b_p.D103V, was previously found in a patient with a history of proarrhythmic conditions with progressive atrial standstill as well as cognitive and motor deficits accompanying structural brain abnormalities. We investigated whether β1 or β1b subunits carrying this mutation affect Na_V1.5 and/or Na_V1.1 currents using a whole cell patch-clamp technique in tsA201 cells. We observed a decrease in sodium current density in cells co-expressing Na_V1.5 or Na_V1.1 and β1^D103V compared to β1^WT. Interestingly, β1b^D103V did not affect Na_V1.1 sodium current density but induced a positive shift in the voltage dependence of inactivation and a faster recovery from inactivation compared to β1b^WT. The β1b^D103V isoform did not affect Na_V1.5 current properties. Although the SCN1B_c.308A>T mutation may not be the sole cause of the patient’s symptoms, we observed a clear loss of function in both cardiac and brain sodium channels. Our results suggest that the mutant β1 and β1b subunits play a fundamental role in the observed electrical dysfunction.