Presynaptic hyperexcitability reversed by positive allosteric modulation of a GABABR epilepsy variant.

GABABRs are key membrane proteins that continually adapt the excitability of the nervous system. These G-protein coupled receptors are activated by the brain's premier inhibitory neurotransmitter GABA. They are obligate heterodimers composed of GABA-binding GABABR1 and G-protein-coupling GABABR2 subunits.

CGP7930 - An allosteric modulator of GABARs, GABARs and inwardly-rectifying potassium channels.

Type-A and -B GABA receptors (GABARs/GABARs) control brain function and behaviour by fine tuning neurotransmission. Over-time these receptors have become important therapeutic targets for treating neurodevelopmental and neuropsychiatric disorders. Several positive allosteric modulators (PAMs) of GABARs have reached the clinic and selective targeting of receptor subtypes is crucial.

Phosphorylation of neuroligin-2 by PKA regulates its cell surface abundance and synaptic stabilization.

The trans-synaptic adhesion molecule neuroligin-2 (NL2) is essential for the development and function of inhibitory synapses. NL2 recruits the postsynaptic scaffold protein gephyrin, which, in turn, stabilizes γ-aminobutyric acid type A receptors (GABARs) in the postsynaptic domain. Thus, the amount of NL2 at the synapse can control synaptic GABAR concentration to tune inhibitory neurotransmission efficacy.

AKAP79 enables calcineurin to directly suppress protein kinase A activity.

Interplay between the second messengers cAMP and Ca is a hallmark of dynamic cellular processes. A common motif is the opposition of the Ca-sensitive phosphatase calcineurin and the major cAMP receptor, protein kinase A (PKA). Calcineurin dephosphorylates sites primed by PKA to bring about changes including synaptic long-term depression (LTD).

Acute Splenic Sequestration Crisis in Hemoglobin SC Disease: Efficiency of Red Cell Exchange.

Acute splenic sequestration crisis (ASSC) is recognized as a serious complication of sickle cell disease in children. ASSC presents with progressive splenic enlargement, transfusion-dependent anemia, and, eventually, circulatory compromise. ASSC is rare in adult patients, thus making its management and outcome in adults not well-defined.

Radiologic Manifestations of Pulmonary Vein Ablation Complications: A Pictorial Review.

In patients with atrial fibrillation refractory to drug therapy and cardioversion, pulmonary vein ablation is an alternative treatment that eradicates arrhythmogenic activity originating in the muscles of the pulmonary veins. While this procedure has a low incidence of significant complications, iatrogenic injuries are possible. Through multimodality pictorial examples utilizing computed tomography, nuclear medicine, fluoroscopy, and chest radiographs, the complications associated with pulmonary vein ablation will be reviewed.

Differential Coassembly of α1-GABARs Associated with Epileptic Encephalopathy.

GABA receptors (GABARs) are profoundly important for controlling neuronal excitability. Spontaneous and familial mutations to these receptors feature prominently in excitability disorders and neurodevelopmental deficits following disruption to GABA-mediated inhibition. Recent genotyping of an individual with severe epilepsy and Williams-Beuren syndrome identified a frameshifting variant in a major GABAR gene, This truncated the α1 subunit between the third and fourth transmembrane domains and introduced 24 new residues forming the mature protein, α1* Cell surface expression of mutant murine GABARs is severely impaired compared with WT, due to retention in the endoplasmic reticulum.

GABAR isoform and subunit structural motifs determine synaptic and extrasynaptic receptor localisation.

GABA receptors (GABARs) are the principal inhibitory neurotransmitter receptors in the central nervous system. They control neuronal excitability by synaptic and tonic forms of inhibition mostly mediated by different receptor subtypes located in specific cell membrane subdomains. A consensus suggests that α1-3βγ comprise synaptic GABARs, whilst extrasynaptic α4βδ, α5βγ and αβ isoforms largely underlie tonic inhibition.

Cell surface expression of homomeric GABA receptors depends on single residues in subunit transmembrane domains.

Cell surface expression of type A GABA receptors (GABARs) is a critical determinant of the efficacy of inhibitory neurotransmission. Pentameric GABARs are assembled from a large pool of subunits according to precise co-assembly rules that limit the extent of receptor structural diversity. These rules ensure that particular subunits, such as ρ1 and β3, form functional cell surface ion channels when expressed alone in heterologous systems, whereas other brain-abundant subunits, such as α and γ, are retained within intracellular compartments.

Wnt Signaling Mediates LTP-Dependent Spine Plasticity and AMPAR Localization through Frizzled-7 Receptors.

The structural and functional plasticity of synapses is critical for learning and memory. Long-term potentiation (LTP) induction promotes spine growth and AMPAR accumulation at excitatory synapses, leading to increased synaptic strength. Glutamate initiates these processes, but the contribution from extracellular modulators is not fully established.

Epilepsy and intellectual disability linked protein Shrm4 interaction with GABARs shapes inhibitory neurotransmission.

Shrm4, a protein expressed only in polarized tissues, is encoded by the KIAA1202 gene, whose mutations have been linked to epilepsy and intellectual disability. However, a physiological role for Shrm4 in the brain is yet to be established. Here, we report that Shrm4 is localized to synapses where it regulates dendritic spine morphology and interacts with the C terminus of GABA receptors (GABARs) to control their cell surface expression and intracellular trafficking via a dynein-dependent mechanism.

Phospho-dependent Accumulation of GABABRs at Presynaptic Terminals after NMDAR Activation.

Here, we uncover a mechanism for regulating the number of active presynaptic GABAB receptors (GABABRs) at nerve terminals, an important determinant of neurotransmitter release. We find that GABABRs gain access to axon terminals by lateral diffusion in the membrane. Their relative accumulation is dependent upon agonist activation and the presence of the two distinct sushi domains that are found only in alternatively spliced GABABR1a subunits.

Utility of (99m)Tc RBC Scintigraphy in Diagnosing Parotid Venous Malformations.

Venous malformations of the parotid glands are uncommon and can be difficult to confirm on routine anatomical imaging alone because of overlap of imaging features with other more common parotid lesions. (99m)Tc RBC scans combined with SPECT/CT offer a noninvasive way to diagnose parotid venous malformations without the need for biopsy. Combined with anatomical findings of phleboliths (when present), the diagnosis can be reliably determined.

Brief report: isogenic induced pluripotent stem cell lines from an adult with mosaic down syndrome model accelerated neuronal ageing and neurodegeneration.

Trisomy 21 (T21), Down Syndrome (DS) is the most common genetic cause of dementia and intellectual disability. Modeling DS is beginning to yield pharmaceutical therapeutic interventions for amelioration of intellectual disability, which are currently being tested in clinical trials. DS is also a unique genetic system for investigation of pathological and protective mechanisms for accelerated ageing, neurodegeneration, dementia, cancer, and other important common diseases.

Snake neurotoxin α-bungarotoxin is an antagonist at native GABA(A) receptors.

The snake neurotoxin α-bungarotoxin (α-Bgtx) is a competitive antagonist at nicotinic acetylcholine receptors (nAChRs) and is widely used to study their function and cell-surface expression. Increasingly, α-Bgtx is also used as an imaging tool for fluorophore-labelling studies, and given the structural conservation within the pentameric ligand-gated ion channel family, we assessed whether α-Bgtx could bind to recombinant and native γ-aminobutyric type-A receptors (GABAARs). Applying fluorophore-linked α-Bgtx to recombinant αxβ1/2γ2 GABAARs expressed in HEK-293 cells enabled clear cell-surface labelling of α2β1/2γ2 contrasting with the weaker staining of α1/4β1/2γ2, and no labelling for α3/5/6β1/2γ2.

Photo-antagonism of the GABAA receptor.

Neurotransmitter receptor trafficking is fundamentally important for synaptic transmission and neural network activity. GABAA receptors and inhibitory synapses are vital components of brain function, yet much of our knowledge regarding receptor mobility and function at inhibitory synapses is derived indirectly from using recombinant receptors, antibody-tagged native receptors and pharmacological treatments. Here we describe the use of a set of research tools that can irreversibly bind to and affect the function of recombinant and neuronal GABAA receptors following ultraviolet photoactivation.

Tracking cell surface mobility of GPCRs using α-bungarotoxin-linked fluorophores.

GABA(B) receptors are G-protein-coupled receptors (GPCRs) that are activated by GABA, the principal inhibitory neurotransmitter in the central nervous system. Cell surface mobility of GABA(B) receptors is a key determinant of the efficacy of slow and prolonged synaptic inhibition initiated by GABA. Therefore, experimentally monitoring receptor mobility and how this can be regulated is of primary importance for understanding the roles of GABA(B) receptors in the brain, and how they may be therapeutically exploited.

Sushi domains confer distinct trafficking profiles on GABAB receptors.

GABA(B) receptors mediate slow inhibitory neurotransmission in the brain and feature during excitatory synaptic plasticity, as well as various neurological conditions. These receptors are obligate heterodimers composed of GABA(B)R1 and R2 subunits. The two predominant R1 isoforms differ by the presence of two complement control protein modules or Sushi domains (SDs) in the N terminus of R1a.

Gamma-aminobutyric acid type B (GABA(B)) receptor internalization is regulated by the R2 subunit.

γ-Aminobutyric acid type B (GABA(B)) receptors are important for slow synaptic inhibition in the CNS. The efficacy of inhibition is directly related to the stability of cell surface receptors. For GABA(B) receptors, heterodimerization between R1 and R2 subunits is critical for cell surface expression and signaling, but how this determines the rate and extent of receptor internalization is unknown.

Transfer of antibiotic resistance by transformation with eDNA within oral biofilms.

We demonstrate that live donor Veillonella dispar cells can transfer the conjugative transposon Tn916 to four different Streptococcus spp. recipients in a multispecies oral consortium growing as a biofilm in a constant depth film fermentor. Additionally, we demonstrate that purified V.