The m1 muscarinic acetylcholine receptor transactivates the EGF receptor to modulate ion channel activity

Intracellular tyrosine kinases link the G protein-coupled m1 muscarinic acetylcholine receptor (mAChR) to multiple cellular responses. However, the mechanisms by which m1 mAChRs stimulate tyrosine kinase activity and the identity of the kinases within particular signaling pathways remain largely unknown. We show that the epidermal growth factor receptor (EGFR), a single transmembrane receptor tyrosine kinase, becomes catalytically active and dimerized through an m1 mAChR-regulated pathway that requires protein kinase C, but is independent of EGF. Finally, we demonstrate that transactivation of the EGFR plays a major role in a pathway linking m1 mAChRs to modulation of the Kv1.2 potassium channel. These results demonstrate a ligand-independent mechanism of EGFR transactivation by m1 mAChRs and reveal a novel role for these growth factor receptors in the regulation of ion channels by G protein-coupled receptors.     

Dantrolene inhibition of sarcoplasmic reticulum Ca2+ release by direct and specific action at skeletal muscle ryanodine receptors

The skeletal muscle relaxant dantrolene inhibits the release of Ca2+ from the sarcoplasmic reticulum during excitation-contraction coupling and suppresses the uncontrolled Ca2+ release that underlies the skeletal muscle pharmacogenetic disorder malignant hyperthermia; however, the molecular mechanism by which dantrolene selectively affects skeletal muscle Ca2+ regulation remains to be defined. Here we provide evidence of a high-affinity, monophasic inhibition by dantrolene of ryanodine receptor Ca2+ channel function in isolated sarcoplasmic reticulum vesicles prepared from malignant hyperthermia-susceptible and normal pig skeletal muscle. In media simulating resting myoplasm, dantrolene increased the half-time for 45Ca2+ release from both malignant hyperthermia and normal vesicles approximately 3.5-fold and inhibited sarcoplasmic reticulum vesicle [3H]ryanodine binding (Ki approximately 150 nM for both malignant hyperthermia and normal). Inhibition of vesicle [3H]ryanodine binding by dantrolene was associated with a decrease in the extent of activation by both calmodulin and Ca2+. Dantrolene also inhibited [3H]ryanodine binding to purified skeletal muscle ryanodine receptor protein reconstituted into liposomes. In contrast, cardiac sarcoplasmic reticulum vesicle 45Ca2+ release and [3H]ryanodine binding were unaffected by dantrolene. Together, these results demonstrate selective effects of dantrolene on skeletal muscle ryanodine receptors that are consistent with the actions of dantrolene in vivo and suggest a mechanism of action in which dantrolene may act directly at the skeletal muscle ryanodine receptor complex to limit its activation by calmodulin and Ca2+. The potential implications of these results for understanding how dantrolene and malignant hyperthermia mutations may affect the voltage-dependent activation of Ca2+ release in intact skeletal muscle are discussed.     

A novel ultracompact two-mode-interference wavelength division multiplexer for 1.5-/spl mu/m operation

A novel ultracompact 2/spl times/2 wavelength division multiplexer (WDM) for 1.55-/spl mu/m operation based on highly dispersive two-mode interference (TMI) was designed, theoretically modeled, and verified using a finite-difference-time-domain (FDTD) method. A two-moded waveguide assisted with a dispersive tooth-shaped grating provided a mode-dependent reflection band of central wavelength at 1.55 /spl mu/m. The wavelengths of 1538 and 1572 nm that were at the band edges and had the lowest reflection losses and relatively high dispersion were selected for wavelength multiplexing. The result showed that the wavelengths were separated by grating dispersion in a coupler length of 75 /spl mu/m which was much shorter than the required length of 1.1 mm in a regular TMI multiplexer of no grating. Insertion loss of about 1.7 dB and channel contrast of about 12 dB were achieved.     

Effect of Cu concentration on the reactions between Sn-Ag-Cu solders and Ni

The reaction between the Sn-Ag-Cu solders and Ni at 250°C for 10 min and 25 h was studied. Nine different Sn-Ag-Cu solders, with the Ag concentration fixed at 3.9 wt.% and Cu concentrations varied between 0.0–3.0 wt.%, were used. When the reaction time was 10 min, the reactions strongly depended on the Cu concentration. At low-Cu concentrations (≦0.2 wt.%), only a continuous (Ni_1−xCu_x)₃Sn₄ layer formed at the interface. When the Cu concentration increased to 0.4 wt.%, a continuous (Ni_1−xCu_x)₃Sn₄ layer and a small amount of discontinuous (Cu_1−yNi_y)₆Sn₅ particles formed at the interface. When the Cu concentration increased to 0.5 wt.%, the amount of (Cu_1−yNi_y)₆Sn₅ increased and (Cu_1−yNi₆)₆Sn₅ became a continuous layer. Beneath this (Cu_1−yNi_y)₆Sn₅ layer was a very thin but continuous layer of (Ni_1−xCu_x)₃Sn₄. At higher Cu concentrations (0.6–3.0 wt.%), (Ni_1−xCu_x)₃Sn₄ disappeared, and only (Cu_1−yNi_y)₆Sn₅ was present. The reactions at 25 h also depended strongly on the Cu concentration, proving that the strong concentration dependence was not a transient phenomenon limited to a short reaction time. The findings of this study were rationalized using the Cu-Ni-Sn isotherm. This study shows that precise control over the Cu concentration in solders is needed to produce consistent results.     

Time and Temperature Factors in Construction of Rock Strength Criteria

Using the synthesis of the kinetic concept on solid strength and the Coulomb - Mohr strength theory as the base, the failure conditions taking into account the time and temperature factors are obtained.     

Lipase‐catalyzed dynamic kinetic resolution of (R,S)‐fenoprofen thioester in isooctane

A lipase‐catalyzed enantioselective hydrolysis process under in situ racemization of the remaining (R)‐thioetser substrate with trioctylamine as the catalyst was developed for the production of (S)‐fenoprofen from (R,S)‐fenoprofen 2,2,2‐trifluoroethyl thioester in isooctane. Detailed investigations of trioctylamine concentration on the enzyme activation and the kinetic behavior of the thioester in racemization and enzymatic reactions were conducted, in which good agreement between the experimental data and theoretical results was observed. © 2002 Society of Chemical Industry