Molecular mechanisms of the GABA type A receptor function.

The GABA type A receptor (GABAR) belongs to the family of pentameric ligand-gated ion channels and plays a key role in inhibition in adult mammalian brains. Dysfunction of this macromolecule may lead to epilepsy, anxiety disorders, autism, depression, and schizophrenia. GABAR is also a target for multiple physiologically and clinically relevant modulators, such as benzodiazepines (BDZs), general anesthetics, and neurosteroids.

Mutation of valine 53 at the interface between extracellular and transmembrane domains of the β principal subunit affects the GABA receptor gating.

GABA receptors (gamma-aminobutyric acid type A receptors) are pentameric ligand-gated ion channels mediating inhibition in adult mammalian brains. Their static structure has been intensely studied in the past years but the underlying molecular activatory mechanisms remain obscure. The interface between extracellular and transmembrane domains has been recognized as a key player in the receptor gating.

Glycine substitution of α1F64 residue at the loop D of GABA receptor impairs gating - Implications for importance of binding site-channel gate linker rigidity.

GABA receptors (GABARs) play a crucial role in mediating inhibition in adult mammalian brains. In the recent years, an impressive progress in revealing the static structure of GABARs was achieved but the molecular mechanisms underlying their conformational transitions remain elusive. Phenylalanine 64 (α1F64) is located at the loop D of the orthosteric binding site of GABAR and was found to directly interact with GABA molecule.

The β subunit E155 residue as a proton sensor at the binding site on GABA type A receptors.

GABA type A receptor plays a key role in inhibitory signaling in the adult central nervous system. This receptor can be modulated by protons but the underlying molecular mechanisms have not been fully explored. To find possible pH-sensor residues, a comparative study for proton-activated GLIC channel and αβγ GABA receptor was performed and pK 's of respective residues were estimated by numerical algorithms which consider local interactions.

GABA Receptor βE155 Residue Located at the Agonist-Binding Site Is Involved in the Receptor Gating.

GABA receptors (GABARs) play a crucial role in mediating inhibition in the adult brain. In spite of progress in describing (mainly) the static structures of this receptor, the molecular mechanisms underlying its activation remain unclear. It is known that in the αβγ receptors, the mutation of the βE155 residue, at the orthosteric binding site, strongly impairs the receptor activation, but the molecular and kinetic mechanisms of this effect remain elusive.

Distinct Modulation of Spontaneous and GABA-Evoked Gating by Flurazepam Shapes Cross-Talk Between Agonist-Free and Liganded GABA Receptor Activity.

GABA receptors (GABARs) play a crucial inhibitory role in the CNS. Benzodiazepines (BDZs) are positive modulators of specific subtypes of GABARs, but the underlying mechanism remains obscure. Early studies demonstrated the major impact of BDZs on binding and more recent investigations indicated gating, but it is unclear which transitions are affected.

Comparison of kinetic and pharmacological profiles of recombinant α1γ2L and α1β2γ2L GABAA receptors - A clue to the role of intersubunit interactions.

The fastest inhibitory mechanism in the CNS is mediated by ionotropic GABAA receptors and it is known that subunit composition critically determines their properties. While a typical GABAA receptor consists of two α, two β and one γ/δ subunit, there are some exceptions, e.g.

Dietary acetylenic oxylipin falcarinol differentially modulates GABAA receptors.

The dietary oxylipins falcarinol (1a) and falcarindiol (1b) trap thiols by direct nucleophilic addition to their diyne system, but despite this, only falcarinol (1a) is a reversible agonist of cannabinoid receptors, providing a rationale for comparing their activity also on other neuronal targets. Because GABAA receptors (GABAARs) are exquisitely sensitive to polyacetylenic oxylipins in terms of either potentiation (falcarindiol, 1b) or inhibition (oenanthotoxin, 2a), the activity of 1a was investigated on synaptic (α1β2γ2L) and extrasynaptic (α1β2δ and α1β2) subtypes of GABAARs. Falcarinol (1a) significantly enhanced the amplitude of currents mediated by α1β2γ2L receptors, but this effect was associated with a use-dependent block.

α1F64 Residue at GABA(A) receptor binding site is involved in gating by influencing the receptor flipping transitions.

GABA receptors (GABAARs) mediate inhibition in the adult brain. These channels are heteropentamers and their ligand binding sites are localized at the β+ / α- interfaces. As expected, mutations of binding-site residues affect binding kinetics but accumulating evidence indicates that gating is also altered, although the underlying mechanisms are unclear.

Monoterpene α-thujone exerts a differential inhibitory action on GABA(A) receptors implicated in phasic and tonic GABAergic inhibition.

A monoterpene ketone, α-thujone originally attracted attention as a major natural ingredient of absinthe and was suspected to cause adverse effects such as hallucinations and seizures in persons excessively consuming this beverage. Although subsequent studies ruled out any major role of α-thujone in the "absynthism", it was found that at high doses it may induce epileptic activity pointing to an interaction with GABAergic inhibition. Indeed, subsequent studies, including those from this laboratory, showed that α-thujone inhibits GABAergic currents.

Falcarindiol allosterically modulates GABAergic currents in cultured rat hippocampal neurons.

Falcarindiol (1), a C-17 polyacetylenic diol, shows a pleiotropic profile of bioactivity, but the mechanism(s) underlying its actions are largely unknown. Large amounts of 1 co-occur in water hemlock (Oenanthe crocata) along with the convulsant polyacetylenic toxin oenanthotoxin (2), a potent GABA(A) receptor (GABA(A)R) inhibitor. Since these compounds are structurally and biogenetically related, it was considered of interest to evaluate whether 1 could affect GABAergic activity, and for this purpose a model of hippocampal cultured neurons was used.

Modulation of GABAergic synaptic currents and current responses by α-thujone and dihydroumbellulone.

α-Thujone (1a), a constituent of wormwood, has been suspected to cause adverse psychoactive reactions in addicted drinkers of absinthe. While the content of 1a in absinthe is too low for such effects, at higher doses it can indeed induce seizures and inhibit GABA(A) receptors (GABA(A)Rs). The effect of 1a on GABAergic synaptic currents and the mechanisms by which it modulates GABA(A)Rs remain unknown.

Oligomerization of ZFYVE27 (Protrudin) is necessary to promote neurite extension.

ZFYVE27 (Protrudin) was originally identified as an interacting partner of spastin, which is most frequently mutated in hereditary spastic paraplegia. ZFYVE27 is a novel member of FYVE family, which is implicated in the formation of neurite extensions by promoting directional membrane trafficking in neurons. Now, through a yeast two-hybrid screen, we have identified that ZFYVE27 interacts with itself and the core interaction region resides within the third hydrophobic region (HR3) of the protein.

Apo A-II participates in HDL-liposome interaction by the formation of new pre-β mobility particles and the modification of liposomes.

Interaction between high density lipoproteins (HDL) and liposomes results in both a structural modification of HDL and the generation of new pre-β HDL-like particles. Here, phosphatidylcholine liposomes and human HDL were incubated at liposomal phospholipid/HDL phospholipid (L-PL/HDL-PL) ratios of 1:1, 3:1 and 5:1 with a subsequent assessment of the distribution of apolipoprotein (apo) A-I, apo A-II, free cholesterol (FC) and PL between newly generated pre-β mobility lipoproteins and non-disrupted liposomes. Both at L-PL/HDL-PL ratios of 3:1 and 5:1 the fraction of liposomal-derived PL associated with pre-β fraction was significantly higher than those accepted by α-HDL.

[Disturbances of lipoprotein metabolism in metabolic syndrome].

Dyslipidemia in metabolic syndrome (MS), called the atherogenic triad, includes elevated levels of plasma triglycerides (TGs), low levels of HDL-cholesterol (HDL-CH), and the presence of small dense low-density lipoproteins (sdLDLs) with normal or slightly elevated LDL-CH levels. Insulin resistance drives the increase in the three main sources of TG for VLDL synthesis: fatty-acid flux from adipose tissue, de novo lipogenesis, and uptake of remnant lipoproteins. Overproduction of VLDL, predominantly triglyceride-rich large VLDL1 particles, induces the cascade of events which lead to abnormalities of other plasma lipoproteins.