PAR1-mediated Non-periodical Synchronized Calcium Oscillations in Human Mesangial Cells.

Mesangial cells offer structural support to the glomerular tuft and regulate glomerular capillary flow through their contractile capabilities. These cells undergo phenotypic changes, such as proliferation and mesangial expansion, resulting in abnormal glomerular tuft formation and reduced capillary loops. Such adaptation to the changing environment is commonly associated with various glomerular diseases, including diabetic nephropathy and glomerulonephritis.

4-(Azolyl)-Benzamidines as a Novel Chemotype for ASIC1a Inhibitors.

Acid-sensing ion channels (ASICs) play a key role in the perception and response to extracellular acidification changes. These proton-gated cation channels are critical for neuronal functions, like learning and memory, fear, mechanosensation and internal adjustments like synaptic plasticity. Moreover, they play a key role in neuronal degeneration, ischemic neuronal injury, seizure termination, pain-sensing, etc.

Integrated workflow for the identification of new GABA R positive allosteric modulators based on the in silico screening with further in vitro validation. Case study using Enamine's stock chemical space.

Numerous studies reported an association between GABA R subunit genes and epilepsy, eating disorders, autism spectrum disorders, neurodevelopmental disorders, and bipolar disorders. This study was aimed to find some potential positive allosteric modulators and was performed by combining the in silico approach with further in vitro evaluation of its real activity. We started from the GABA R-diazepam complexes and assembled a lipid embedded protein ensemble to refine it via molecular dynamics (MD) simulation.

Acid-sensing ion channel blocker diminazene facilitates proton-induced excitation of afferent nerves in a similar manner that Na/H exchanger blockers do.

Tissue acidification causes sustained activation of primary nociceptors, which causes pain. In mammals, acid-sensing ion channels (ASICs) are the primary acid sensors; however, Na/H exchangers (NHEs) and TRPV1 receptors also contribute to tissue acidification sensing. ASICs, NHEs, and TRPV1 receptors are found to be expressed in nociceptive nerve fibers.

Temperature increase significantly enhances nociceptive responses of C-fibers to ATP, high K, and acidic pH in mice.

It is well established that temperature affects the functioning of almost all biomolecules and, consequently, all cellular functions. Here, we show how temperature variations within a physiological range affect primary afferents' spontaneous activity in response to chemical nociceptive stimulation. An mouse hind limb skin-saphenous nerve preparation was used to study the temperature dependence of single C-mechanoheat (C-MH) fibers' spontaneous activity.

Triggering of Major Brain Disorders by Protons and ATP: The Role of ASICs and P2X Receptors.

Adenosine triphosphate (ATP) is well-known as a universal source of energy in living cells. Less known is that this molecule has a variety of important signaling functions: it activates a variety of specific metabotropic (P2Y) and ionotropic (P2X) receptors in neuronal and non-neuronal cell membranes. So, a wide variety of signaling functions well fits the ubiquitous presence of ATP in the tissues.

Modelling of an autonomous Nav1.5 channel system as a part of in silico pharmacology study.

A homology model of Nav1.5, based mainly on the crystal structures of Nav1.2/1.

Mecamylamine inhibits seizure-like activity in CA1-CA3 hippocampus through antagonism to nicotinic receptors.

Cholinergic modulation of hippocampal network function is implicated in multiple behavioral and cognitive states. Activation of nicotinic and muscarinic acetylcholine receptors affects neuronal excitability, synaptic transmission and rhythmic oscillations in the hippocampus. In this work, we studied the ability of the cholinergic system to sustain hippocampal epileptiform activity independently from glutamate and GABA transmission.

Acid-Sensing Ion Channels: Focus on Physiological and Some Pathological Roles in the Brain.

Acid-sensing ion channels (ASICs) are Na+-permeable ion channels activated by protons and predominantly expressed in the nervous system. ASICs act as pH sensors leading to neuronal excitation. At least eight different ASIC subunits (including ASIC1a, ASIC1b, ASIC2a, ASIC2b, ASIC3, ASIC4, ASIC5) are encoded by five genes (ASIC1-ASIC5).

Bilirubin enhances the activity of ASIC channels to exacerbate neurotoxicity in neonatal hyperbilirubinemia in mice.

Neonatal hyperbilirubinemia is a common clinical condition that can lead to brain encephalopathy, particularly when concurrent with acidosis due to infection, ischemia, and hypoxia. The prevailing view is that acidosis increases the permeability of the blood-brain barrier to bilirubin and exacerbates its neurotoxicity. In this study, we found that the concentration of the cell death marker, lactate dehydrogenase (LDH) in cerebrospinal fluid (CSF), is elevated in infants with both hyperbilirubinemia and acidosis and showed stronger correlation with the severity of acidosis rather than increased bilirubin concentration.

Protein Kinase C Lambda Mediates Acid-Sensing Ion Channel 1a-Dependent Cortical Synaptic Plasticity and Pain Hypersensitivity.

Chronic pain is a serious debilitating disease for which effective treatment is still lacking. Acid-sensing ion channel 1a (ASIC1a) has been implicated in nociceptive processing at both peripheral and spinal neurons. However, whether ASIC1a also contributes to pain perception at the supraspinal level remains elusive.

Novel Potent Orthosteric Antagonist of ASIC1a Prevents NMDAR-Dependent LTP Induction.

Acid sensing ion channels 1a (ASIC1a) are of crucial importance in numerous physiological and pathological processes in the brain. Here we demonstrate that novel 2-oxo-2H-chromene-3-carboxamidine derivative 5b, designed with molecular modeling approach, inhibits ASIC1a currents with an apparent IC50 of 27 nM when measured at pH 6.7.

Neuraminidase inhibition primes short-term depression and suppresses long-term potentiation of synaptic transmission in the rat hippocampus.

Neuraminidase (NEU) is a key enzyme that cleaves negatively charged sialic acid residues from membrane proteins and lipids. Clinical and basic science studies have shown that an imbalance in NEU metabolism or changes in NEU activity due to various pathological conditions parallel with behavior and cognitive impairment. It has been suggested that the decreases of NEU activity could cause serious neurological consequences.

Persistent sodium current properties in hippocampal CA1 pyramidal neurons of young and adult rats.

Persistent tetrodotoxin-sensitive sodium current (INaP) plays an important role in cellular and neuronal network excitability in physiological conditions and under different pathological circumstances. However, developmental changes in INaP properties remain largely unclear. In the present study using whole cell patch clamp technique we evaluated INaP properties in CA1 hippocampal pyramidal neurons isolated from young (postnatal day (P) 12-16) and adult (P60-75) rats.

Surface charge impact in low-magnesium model of seizure in rat hippocampus.

Putative mechanisms of induction and maintenance of seizure-like activity (SLA) in the low Mg(2+) model of seizures are: facilitation of NMDA receptors and decreased surface charge screening near voltage-gated channels. We have estimated the role of such screening in the early stages of SLA development at both physiological and room temperatures. External Ca(2+) and Mg(2+) promote a depolarization shift of the sodium channel voltage sensitivity; when examined in hippocampal pyramidal neurons, the effect of Ca(2+) was 1.