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Reduced Inhibition (reduced + inhibition)

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Medical Sciences	50%

Selected Abstracts

Reduced inhibition of cortical glutamate and GABA release by halothane in mice lacking the K+ channel, TREK-1

BRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2007
R I Westphalen
Background and purpose: Deletion of TREK-1, a two-pore domain K+ channel (K2P) activated by volatile anaesthetics, reduces volatile anaesthetic potency in mice, consistent with a role for TREK-1 as an anaesthetic target. We used TREK-1 knockout mice to examine the presynaptic function of TREK-1 in transmitter release and its role in the selective inhibition of glutamate vs GABA release by volatile anaesthetics. Experimental approach: The effects of halothane on 4-aminopyridine-evoked and basal [3H]glutamate and [14C]GABA release from cerebrocortical nerve terminals isolated from TREK-1 knockout (KO) and littermate wild-type (WT) mice were compared. TREK-1 was quantified by immunoblotting of nerve terminal preparations. Key results: Deletion of TREK-1 significantly reduced the potency of halothane inhibition of 4-aminopyridine-evoked release of both glutamate and GABA without affecting control evoked release or the selective inhibition of glutamate vs GABA release. TREK-1 deletion also reduced halothane inhibition of basal glutamate release, but did not affect basal GABA release. Conclusions and implications: The reduced sensitivity of glutamate and GABA release to inhibition by halothane in TREK-1 KO nerve terminals correlates with the reduced anaesthetic potency of halothane in TREK-1 KO mice observed in vivo. A presynaptic role for TREK-1 was supported by the enrichment of TREK-1 in isolated nerve terminals determined by immunoblotting. This study represents the first evidence for a link between an anaesthetic-sensitive 2-pore domain K+ channel and presynaptic function, and provides further support for presynaptic mechanisms in determining volatile anaesthetic action. British Journal of Pharmacology (2007) 152, 939,945; doi:10.1038/sj.bjp.0707450; published online 10 September 2007 [source]

Amprenavir complexes with HIV-1 protease and its drug-resistant mutants altering hydrophobic clusters

FEBS JOURNAL, Issue 18 2010
Chen-Hsiang Shen
The structural and kinetic effects of amprenavir (APV), a clinical HIV protease (PR) inhibitor, were analyzed with wild-type enzyme and mutants with single substitutions of V32I, I50V, I54V, I54M, I84V and L90M that are common in drug resistance. Crystal structures of the APV complexes at resolutions of 1.02,1.85 Å reveal the structural changes due to the mutations. Substitution of the larger side chains in PRV32I, PRI54M and PRL90M resulted in the formation of new hydrophobic contacts with flap residues, residues 79 and 80, and Asp25, respectively. Mutation to smaller side chains eliminated hydrophobic interactions in the PRI50V and PRI54V structures. The PRI84V,APV complex had lost hydrophobic contacts with APV, the PRV32I,APV complex showed increased hydrophobic contacts within the hydrophobic cluster and the PRI50V complex had weaker polar and hydrophobic interactions with APV. The observed structural changes in PRI84V,APV, PRV32I,APV and PRI50V,APV were related to their reduced inhibition by APV of six-, 10- and 30-fold, respectively, relative to wild-type PR. The APV complexes were compared with the corresponding saquinavir complexes. The PR dimers had distinct rearrangements of the flaps and 80,s loops that adapt to the different P1, groups of the inhibitors, while maintaining contacts within the hydrophobic cluster. These small changes in the loops and weak internal interactions produce the different patterns of resistant mutations for the two drugs. Structured digital abstract ,,MINT-7966480: HIV-1 PR (uniprotkb:P03366) and HIV-1 PR (uniprotkb:P03366) bind (MI:0407) by x-ray crystallography (MI:0114) [source]

Effects of Distraction Versus Spatial Discrimination on Laser-Evoked Potentials in Migraine

HEADACHE, Issue 3 2008
Marina De Tommaso MD
Objectives., To evaluate whether migraine patients exhibit less inhibition to painful stimuli when distracted from pain as compared to healthy subjects, testing the spatial discrimination of painful stimuli, the performance during the mental arithmetic task used to contrast the discrimination performance and the behavior of N1 and N2-P2 laser-evoked potentials (LEPs) amplitudes during spatial discrimination and during distraction. Methods., Eight migraine patients and 8 healthy controls were examined. During repetitive series of painful laser stimulation of the hand, they had to (1) perform a spatial discrimination task, contrasted by (2) a mental arithmetic task that served as distraction. Results., Patients made 50% to 100% more mistakes than controls in the spatial discrimination task (P < .001) as well as during mental arithmetic (P < .05). Whereas healthy subjects showed a marked decrease of the LEP vertex potential amplitudes during distraction compared to the discrimination task, no such attenuation of LEPs was seen in migraine patients (group × task interaction, P < .05). N1 amplitude exhibited a left-hemisphere dominance in both groups, significantly smaller amplitude in migraine patients, but no significant task modulation. Conclusion., Migraine patients exhibited reduced inhibition by attentional modulation of pain processing, accompanied by impaired spatial discrimination of painful stimuli. [source]

Mitochondrial modulation of Ca2+ sparks and transient KCa currents in smooth muscle cells of rat cerebral arteries

THE JOURNAL OF PHYSIOLOGY, Issue 3 2004
Serguei Y. Cheranov
Mitochondria sequester and release calcium (Ca2+) and regulate intracellular Ca2+ concentration ([Ca2+]i) in eukaryotic cells. However, the regulation of different Ca2+ signalling modalities by mitochondria in smooth muscle cells is poorly understood. Here, we investigated the regulation of Ca2+ sparks, Ca2+ waves and global [Ca2+]i by mitochondria in cerebral artery smooth muscle cells. CCCP (a protonophore; 1 ,m) and rotenone (an electron transport chain complex I inhibitor; 10 ,m) depolarized mitochondria, reduced Ca2+ spark and wave frequency, and elevated global [Ca2+]i in smooth muscle cells of intact arteries. In voltage-clamped (,40 mV) cells, mitochondrial depolarization elevated global [Ca2+]i, reduced Ca2+ spark amplitude, spatial spread and the effective coupling of sparks to large-conductance Ca2+ -activated potassium (KCa) channels, and decreased transient KCa current frequency and amplitude. Inhibition of Ca2+ sparks and transient KCa currents by mitochondrial depolarization could not be explained by a decrease in intracellular ATP or a reduction in sarcoplasmic reticulum Ca2+ load, and occurred in the presence of diltiazem, a voltage-dependent Ca2+ channel blocker. Ru360 (10 ,m), a mitochondrial Ca2+ uptake blocker, and lonidamine (100 ,m), a permeability transition pore (PTP) opener, inhibited transient KCa currents similarly to mitochondrial depolarization. In contrast, CGP37157 (10 ,m), a mitochondrial Na+,Ca2+ exchange blocker, activated these events. The PTP blockers bongkrekic acid and cyclosporin A both reduced inhibition of transient KCa currents by mitochondrial depolarization. These results indicate that mitochondrial depolarization leads to a voltage-independent elevation in global [Ca2+]i and Ca2+ spark and transient KCa current inhibition. Data also suggest that mitochondrial depolarization inhibits Ca2+ sparks and transient KCa currents via PTP opening and a decrease in intramitochondrial [Ca2+]. [source]