Activation of retinoid X receptors protects retinal neurons and pigment epithelial cells from BMAA-induced death.

Exposure to the non-protein amino acid cyanotoxin β-N-methylamino-L-alanine (BMAA), released by cyanobacteria found in many water reservoirs has been associated with neurodegenerative diseases. We previously demonstrated that BMAA induced cell death in both retina photoreceptors (PHRs) and amacrine neurons by triggering different molecular pathways, as activation of NMDA receptors and formation of carbamate-adducts was only observed in amacrine cell death. We established that activation of Retinoid X Receptors (RXR) protects retinal cells, including retina pigment epithelial (RPE) cells from oxidative stress-induced apoptosis.

Development of Magnetic Nanosystems with Potential for the Treatment of Inner Ear Pathologies.

Hearing loss (HL) affects more than 5 % of the global population, with projections indicating an impact of up to 50 % on young individuals in the next years. HL treatments remain limited due to the inner ear's hermeticism. HL often involves inflammatory processes, underscoring the need for enhanced delivery of antiinflammatory agents to the inner ear.

Novel Insights and Perspectives for the Diagnosis and Treatment of Hearing Loss through the Implementation of Magnetic Nanotheranostics.

Hearing loss (HL) is a sensory disability that affects 5 % of the world's population. HL predominantly involves damage and death to the cochlear cells. Currently, there is no cure or specific medications for HL.

Novel variants in outer protein surface of flavin-containing monooxygenase 3 found in an Argentinian case with impaired capacity for trimethylamine N-oxygenation.

Flavin-containing monooxygenase 3 (FMO3) is a polymorphic drug metabolizing enzyme associated with the genetic disorder trimethylaminuria. We phenotyped a white Argentinian 11-year-old girl by medical sensory evaluation. After pedigree analysis with her brother and parents, this proband showed to harbor a new allele p.

Inner Hair Cell and Neuron Degeneration Contribute to Hearing Loss in a DFNA2-Like Mouse Model.

DFNA2 is a progressive deafness caused by mutations in the voltage-activated potassium channel KCNQ4. Hearing loss develops with age from a mild increase in the hearing threshold to profound deafness. Studies using transgenic mice for Kcnq4 expressed in a mixed background demonstrated the implication of outer hair cells at the initial phase.

Analysis of neuronal nicotinic acetylcholine receptor α4β2 activation at the single-channel level.

The neuronal nicotinic acetylcholine receptor α4β2 forms pentameric proteins with two alternate stoichiometries. The high-sensitivity receptor is related to (α4)2(β2)3 stoichiometry while the low-sensitivity receptor to (α4)3(β2)2 stoichiometry. Both subtypes share two binding sites at the α4((+))/β2((-)) interface with high affinity for agonists.

Vestibular role of KCNQ4 and KCNQ5 K+ channels revealed by mouse models.

The function of sensory hair cells of the cochlea and vestibular organs depends on an influx of K(+) through apical mechanosensitive ion channels and its subsequent removal over their basolateral membrane. The KCNQ4 (Kv7.4) K(+) channel, which is mutated in DFNA2 human hearing loss, is expressed in the basal membrane of cochlear outer hair cells where it may mediate K(+) efflux.

Raising cytosolic Cl- in cerebellar granule cells affects their excitability and vestibulo-ocular learning.

Cerebellar cortical throughput involved in motor control comprises granule cells (GCs) and Purkinje cells (PCs), both of which receive inhibitory GABAergic input from interneurons. The GABAergic input to PCs is essential for learning and consolidation of the vestibulo-ocular reflex, but the role of GC excitability remains unclear. We now disrupted the Kcc2 K-Cl cotransporter specifically in either cell type to manipulate their excitability and inhibition by GABA(A)-receptor Cl(-) channels.

The KCNQ5 potassium channel mediates a component of the afterhyperpolarization current in mouse hippocampus.

Mutations in KCNQ2 and KCNQ3 voltage-gated potassium channels lead to neonatal epilepsy as a consequence of their key role in regulating neuronal excitability. Previous studies in the brain have focused primarily on these KCNQ family members, which contribute to M-currents and afterhyperpolarization conductances in multiple brain areas. In contrast, the function of KCNQ5 (Kv7.

The local anaesthetics proadifen and adiphenine inhibit nicotinic receptors by different molecular mechanisms.

Background And Purpose: Many local anaesthetics are non-competitive inhibitors of nicotinic receptors (acetylcholine receptor, AChR). Proadifen induces a high-affinity state of the receptor, but its mechanism of action and that of an analogue, adiphenine, is unknown.

Experimental Approach: We measured the effects of proadifen and adiphenine on single-channel and macroscopic currents of adult mouse muscle AChR (wild-type and mutant).

Role of pairwise interactions between M1 and M2 domains of the nicotinic receptor in channel gating.

The adult form of the nicotinic acetylcholine receptor (AChR) consists of five subunits (alpha(2)betaepsilondelta), each having four transmembrane domains (M1-M4). The atomic model of the nicotinic acetylcholine receptor shows that the pore-lining M2 domains make no extensive contacts with the rest of the transmembrane domains. However, there are several sites where close appositions between segments occur.

Molecular mechanisms and binding site location for the noncompetitive antagonist crystal violet on nicotinic acetylcholine receptors.

We investigated the molecular mechanisms and the binding site location for the fluorophor crystal violet (CrV), a noncompetitive antagonist of the nicotinic acetylcholine receptor (AChR). To this end, radiolabeled competition binding, fluorescence spectroscopy, Schild-type analysis, patch-clamp recordings, and molecular dynamics approaches were used. The results indicate that (i) CrV interacts with the desensitized Torpedo AChR with higher affinity than with the resting state at several temperatures (5-37 degrees C); (ii) CrV-induced inhibition of the phencyclidine (PCP) analogue [(3)H]thienylcyclohexylpiperidine binding to the desensitized or resting AChR is mediated by a steric mechanism; (iii) tetracaine inhibits CrV binding to the resting AChR, probably by a steric mechanism; (iv) barbiturates modulate CrV binding to the resting AChR by an allosteric mechanism; (v) CrV itself induces AChR desensitization; (vi) CrV decreases the peak of macroscopic currents by acting on the resting AChR but without affecting the desensitization rate from the open state; and (vii) two tertiary amino groups from CrV may bind to the alpha1-Glu(262) residues (located at position 20') in the resting state.

Single-channel kinetic analysis of chimeric alpha7-5HT3A receptors.

The receptor chimera alpha7-5HT3A has served as a prototype for understanding the pharmacology of alpha7 neuronal nicotinic receptors, yet its low single channel conductance has prevented studies of the activation kinetics of single receptor channels. In this study, we show that introducing mutations in the M3-M4 cytoplasmic linker of the chimera alters neither the apparent affinity for the agonist nor the EC50 but increases the amplitude of agonist-evoked single channel currents to enable kinetic analysis. Channel events appear as single brief openings flanked by long closings or as bursts of several openings in quick succession.

Coupling of agonist binding to channel gating in an ACh-binding protein linked to an ion channel.

Neurotransmitter receptors from the Cys-loop superfamily couple the binding of agonist to the opening of an intrinsic ion pore in the final step in rapid synaptic transmission. Although atomic resolution structural data have recently emerged for individual binding and pore domains, how they are linked into a functional unit remains unknown. Here we identify structural requirements for functionally coupling the two domains by combining acetylcholine (ACh)-binding protein, whose structure was determined at atomic resolution, with the pore domain from the serotonin type-3A (5-HT3A) receptor.

Mechanistic contributions of residues in the M1 transmembrane domain of the nicotinic receptor to channel gating.

The nicotinic receptor (AChR) is a pentamer of homologous subunits with an alpha(2)betaepsilondelta composition in adult muscle. Each subunit contains four transmembrane domains (M1-M4). Position 15' of the M1 domain is phenylalanine in alpha subunits while it is isoleucine in non-alpha subunits.

Molecular mechanisms of inhibition of nicotinic acetylcholine receptors by tricyclic antidepressants.

In addition to their well known actions on monoamine reuptake, tricyclic antidepressants have been shown to modulate ligand-gated ion channels (LGICs). Since the muscle nicotinic acetylcholine receptor (AChR) has been the model for studying structure-function relationships of LGICs, we analyzed the action of tricyclic antidepressants on this type of AChR at both single-channel and macroscopic current levels. We also determined their effects on ACh equilibrium binding and their interactions with the different conformational states of the AChR.

Nicotinic receptor M3 transmembrane domain: position 8' contributes to channel gating.

The nicotinic acetylcholine receptor (nAChR) is a pentamer of homologous subunits with composition alpha(2)(beta)(epsilon)(delta) in adult muscle. Each subunit contains four transmembrane domains (M1-M4). Position 8' of the M3 domain is phenylalanine in all heteromeric alpha subunits, whereas it is a hydrophobic nonaromatic residue in non-alpha subunits.