Mechanism underlying bupivacaine inhibition of G protein-gated inwardly rectifying K+ channels

Local anesthetics, commonly used for treating cardiac arrhythmias, pain, and seizures, are best known for their inhibitory effects on voltage-gated Na+ channels. Cardiovascular and central nervous system toxicity are unwanted side-effects from local anesthetics that cannot be attributed to the inhibition of only Na+ channels. Here, we report that extracellular application of the membrane-permeant local anesthetic bupivacaine selectively inhibited G protein-gated inwardly rectifying K+ channels (GIRK:Kir3) but not other families of inwardly rectifying K+ channels (ROMK:Kir1 and IRK:Kir2). Bupivacaine inhibited GIRK channels within seconds of application, regardless of whether channels were activated through the muscarinic receptor or directly via coexpressed G protein Gβγ subunits. Bupivacaine also inhibited alcohol-induced GIRK currents in the absence of functional pertussis toxin-sensitive G proteins. The mutated GIRK1 and GIRK2 (GIRK1/2) channels containing the high-affinity phosphatidylinositol 4,5-bisphosphate (PIP2) domain from IRK1, on the other hand, showed dramatically less inhibition with bupivacaine. Surprisingly, GIRK1/2 channels with high affinity for PIP2 were inhibited by ethanol, like IRK1 channels. We propose that membrane-permeant local anesthetics inhibit GIRK channels by antagonizing the interaction of PIP2 with the channel, which is essential for Gβγ and ethanol activation of GIRK channels.

Preliminary memorandum of a portion of the "Benny K" claims, Piute County, Utah /

"November 6, 1951."

Württembergs Söhne in Frankreich 1870/71 : Erinnerungen von Kriegsteilnehmern / gesammelt und herausgegeben von Paul Dorsch

"Mit Titelbild nach einem Original-Aquarell von K. von Schott."

The earliest English translation of the first three books of the De imitatione Christi, now first printed from a ms. in the library of Trinity college, Dublin, with various readings from a ms. in the University library, Cambridge. Also the earliest printed translation of the whole work from a copy in the British museum (Books I-III by William Atkynson, D. D., book IV by the Lady Margaret, mother of K. Henry VII, and countess of Richmond and Derby).

Mode of access: Internet.

Mohammedan "Narratives of the prophets," covering the period from Zacharias to Paul. Turki text with English translation

Reproduced from manuscript copy.

The homilies of S. John Chrysostom, Archbishop of Constantinople, on the First Epistle of St. Paul the Apostle to the Corinthians.

Translated by Hubert Kestell Cornish and John Medley.

Paul Cézanne /

Mode of access: Internet.

Annual message of Governor C.K. Davis to the Legislature of Minnesota, delivered January 7, 1876 ...

At head of title: Executive document, no. 1.

Ein altassyrisches Rechtsbuch/ übersetzt von Hans Ehelolf ; mit einer rechtsgeschichtlichen Einleitung von Paul Koschaker.

Koschaker's introd. appeared as Quellenkntische Untersuchungen zu den altassyrischen Gesetzen, in the Mitteilungen der vorderasiatisch-ägyptischen Gessellschaft, XXVI, Heft 3.--cf. p. 1.

The homilies of S. John Chrysostom, archbishop of Constantinople on the first Epistle of St. Paul the apostle to the Corinthians /

Translated by: Hubert Kestell Cronish and John Medley.

Semëna Poroshina zapiski : sluzhashchīi︠a︡ k istorīi Ego Imperatorskago Vysochestva blagovi︠e︡rnago gosudari︠a︡ t︠s︡esarevicha i velikago kni︠a︡zi︠a︡ Pavla Petrovicha, nasli︠e︡dnika prestolu rossīĭskago.

Mode of access: Internet.

Das leben und die werke der brüder Matthäus und Paul Brill /

Subtitle on added t.-p. : Ein beitrag zur geschichte der landschaftsmalerei um die wende des sechzehnten jahrunderts.

Proteomic analysis of k-casein micro-heterogeneity

The proteome of bovine milk is dominated by just six gene products that constitute approximately 95% of milk protein. Nonetheless, over 150 protein spots can be readily detected following two-dimensional electrophoresis of whole milk. Many of these represent isoforms of the major gene products produced through extensive posttranslational modification. Peptide mass fingerprinting of in-gel tryptic digests (using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) in reflectron mode with alpha-cyano-4-hydroxycinnamic acid as the matrix) identified 10 forms of K-casein with isoelectric point (pl) values from 4.47 to 5.81, but could not distinguish between them. MALDI-TOF MS in linear mode, using sinapinic acid as the matrix, revealed a large tryptic peptide (mass > 5990 Da) derived from the C-terminus that contained all the known sites of genetic variance, phosphorylation and glycosylation. Two genetic variants present as singly or doubly phosphorylated forms could be distinguished using mass data alone. Glycoforms containing a single acidic tetrasaccharide were also identified. The differences in electrophoretic mobility of these isoforms were consistent with the addition of the acidic groups. While more extensively glycosylated forms were also observed, substantial loss of N-acetylneuraminic acid from the glycosyl group was evident in the MALDI spectra such that ions corresponding to the intact glycopeptide were not observed and assignment of the glycoforms was not possible. However, by analysing the pl shifts observed on the two-dimensional gels in conjunction with the MS data, the number of N-acetylneuraminic acid residues, and hence the glycoforms present, could be determined.

“Niemand zeugt für den Zeugen”. Temporalidad y memoria en la poesía de Paul Celan

El artículo analiza cómo Paul Celan, utilizando recursos arreferenciales y antimiméticos propios de la poésie pure y la poesía absoluta, desarrolla un modelo poético en el que la temporalidad y la memoria son determinantes. En el nuevo modelo, el lenguaje no constituye una realidad autónoma e inmanente; antes bien, se concreta en una acción dialógica y remite a una realidad extralingüística. El mismo texto poético configura un espacio del recuerdo, se erige en un lugar de memoria que, a través de las sedimentaciones históricas que arrastra el lenguaje, da testimonio de lo ocurrido.

Ein Besuch der beiden Inseln St. Paul und Amsterdam im Indischen Ocean

von Dr. Carl Scherzer