Altered Calcium Permeability of AMPA Receptor Drives NMDA Receptor Inhibition in the Hippocampus of Murine Obesity Models

Evidence has accumulated that higher consumption of high-fat diets (HFDs) during the juvenile/adolescent period induces altered hippocampal function and morphology; however, the mechanism behind this phenomenon remains elusive. Using high-resolution structural imaging combined with molecular and functional interrogation, a murine model of obesity treated with HFDs for 12 weeks after weaning mice was shown to change in the glutamate-mediated intracellular calcium signaling and activity, including further selective reduction of gray matter volume in the hippocampus associated with memory recall disturbance. Dysregulation of intracellular calcium concentrations was restored by a non-competitive α-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) antagonist, followed by normalization of hippocampal volume and memory recall ability, indicating that AMPARs may serve as an attractive therapeutic target for obesity-associated cognitive decline.

Ketamine induces opposite changes in AMPA receptor calcium permeability in the ventral tegmental area and nucleus accumbens

Ketamine elicits rapid and durable antidepressant actions in treatment-resistant patients with mood disorders such as major depressive disorder and bipolar depression. The mechanisms might involve the induction of metaplasticity in brain regions associated with reward-related behaviors, mood, and hedonic drive, particularly the ventral tegmental area (VTA) and the nucleus accumbens (NAc). We have examined if ketamine alters the insertion of the GluA2 subunit of AMPA receptors (AMPAR), which determines calcium permeability of the channel, at glutamatergic synapses onto dopamine (DA) neurons in the VTA and spiny projection neurons (SPNs) in the Core region of the NAc. Mice received one injection of either saline or a low dose of ketamine 24 h before electrophysiological recordings were performed. We found that GluA2-lacking calcium-permeable (CP) AMPARs were present in DA neurons in the VTA of mice treated with saline, and that ketamine-induced the removal of a fraction of these receptors. In NAc SPNs, ketamine induced the opposite change, i.e., GluA2-lacking CP-AMPARs were inserted at glutamatergic synapses. Ketamine-induced metaplasticity was independent of group I metabotropic glutamate receptors (mGluRs) because an agonist of these receptors had similar effects on glutamatergic transmission in mice treated with saline and in mice treated with ketamine in both VTA DA neurons and in the NAc. Thus, ketamine reduces the insertion of CP-AMPARs in VTA DA neurons and induces their insertion in the NAc. The mechanism by which ketamine elicits antidepressant actions might thus involve an alteration in the contribution of GluA2 to AMPARs thereby modulating synaptic plasticity in the mesolimbic circuit.

NMDA Receptors Subunits, Medical Conditions Involved in, and Their Roles as Drug Targets

In the 1960s, Jeff Watkins and colleagues discovered N-methyl-d-aspartate (NMDA) receptors, and since then, it has been a pharmacodynamic target for many neurological and psychiatric drugs. NMDA is a glutamate receptor and ion channel protein located in nerve cells. There are many subunits for the NMDA receptor. They are all working together in a harmonic pattern to regulate the calcium permeability and the voltage-dependent sensitivity to magnesium influenced by the binding of glutamate as a neurotransmitter. In this paper, a light will be shed on glutamate ionotropic receptor NMDA subunits. There are several names for the GRIN gene, such as GluN. It is proven that GRIN has a significant influence on memory and learning abilities. Interestingly, part of how GRIN executes its function by interacting with other receptors. For example, GRIN counteracts the role of the cAMP response element-binding protein (CREP) receptor, while its function modulated by dopamine D1 receptors. Therefore, Hypo-functioning and mutation of this gene play a pivotal role in developing neurodevelopmental disorders wither it was with or without hyperkinetic movements and with and without seizures, besides several psychotic disorders such as schizophrenia. Hence, NMDA receptors subunits have been a target for therapeutic development for the last years. With the advancements in the genetic and genomic science, investigators are trying to find the alternative splicing of GRIN, understanding location and the distribution of NMDA subunits with deeper lucidity than it is currently. However, that is faced by some challenges. Modifying the NMDA receptor subunits to treat one condition can lead to potential harm effect in another condition because, sometimes, NMDA works complicatedly inversely with many other receptors and neurotransmitters, which will have an impact on the investigators to find the appropriate way to cause no harm.

Claudin-12 Knockout Mice Demonstrate Reduced Proximal Tubule Calcium Permeability

The renal proximal tubule (PT) is responsible for the reabsorption of approximately 65% of filtered calcium, primarily via a paracellular pathway. However, which protein(s) contribute this paracellular calcium pore is not known. The claudin family of tight junction proteins confers permeability properties to an epithelium. Claudin-12 is expressed in the kidney and when overexpressed in cell culture contributes paracellular calcium permeability (PCa). We therefore examined claudin-12 renal localization and its contribution to tubular paracellular calcium permeability. Claudin-12 null mice (KO) were generated by replacing the single coding exon with β-galactosidase from Escherichia coli. X-gal staining revealed that claudin-12 promoter activity colocalized with aquaporin-1, consistent with the expression in the PT. PTs were microperfused ex vivo and PCa was measured. PCa in PTs from KO mice was significantly reduced compared with WT mice. However, urinary calcium excretion was not different between genotypes, including those on different calcium containing diets. To assess downstream compensation, we examined renal mRNA expression. Claudin-14 expression, a blocker of PCa in the thick ascending limb (TAL), was reduced in the kidney of KO animals. Thus, claudin-12 is expressed in the PT, where it confers paracellular calcium permeability. In the absence of claudin-12, reduced claudin-14 expression in the TAL may compensate for reduced PT calcium reabsorption.

Mechanisms governing irritant-evoked activation and calcium modulation of TRPA1

The TRPA1 ion channel is a chemosensory receptor that is critical for detecting noxious chemical agents that elicit or exacerbate pain or itch. Here we use structural and electrophysiological methods to elucidate how a broad class of reactive electrophilic irritants activate TRPA1 through a two-step cysteine modification mechanism that promotes local conformational changes leading to widening of the selectivity filter to enhance calcium permeability and opening of a cytoplasmic gate. We also identify a calcium binding pocket that is remarkably conserved across TRP channel subtypes and accounts for all aspects of calcium-dependent TRPA1 regulation, including potentiation, desensitization, and activation by metabotropic receptors. These findings provide a structural basis for understanding how endogenous or exogenous chemical agents activate a broad-spectrum irritant receptor directly or indirectly through a cytoplasmic second messenger.

A Tmc1 mutation reduces calcium permeability and expression of mechanoelectrical transduction channels in cochlear hair cells

Mechanoelectrical transducer (MET) currents were recorded from cochlear hair cells in mice with mutations of transmembrane channel-like protein TMC1 to study the effects on MET channel properties. We characterized a Tmc1 mouse with a single-amino-acid mutation (D569N), homologous to a dominant human deafness mutation. Measurements were made in both Tmc2 wild-type and Tmc2 knockout mice. By 30 d, Tmc1 pD569N heterozygote mice were profoundly deaf, and there was substantial loss of outer hair cells (OHCs). MET current in OHCs of Tmc1 pD569N mutants developed over the first neonatal week to attain a maximum amplitude one-third the size of that in Tmc1 wild-type mice, similar at apex and base, and lacking the tonotopic size gradient seen in wild type. The MET-channel Ca2+ permeability was reduced 3-fold in Tmc1 pD569N homozygotes, intermediate deficits being seen in heterozygotes. Reduced Ca2+ permeability resembled that of the Tmc1 pM412K Beethoven mutant, a previously studied semidominant mouse mutation. The MET channel unitary conductance, assayed by single-channel recordings and by measurements of current noise, was unaffected in mutant apical OHCs. We show that, in contrast to the Tmc1 M412K mutant, there was reduced expression of the TMC1 D569N channel at the transduction site assessed by immunolabeling, despite the persistence of tip links. The reduction in MET channel Ca2+ permeability seen in both mutants may be the proximate cause of hair-cell apoptosis, but changes in bundle shape and protein expression in Tmc1 D569N suggest another role for TMC1 apart from forming the channel.