Transformation of (µ-η 2 :η 2 -peroxo)dicopper(II) complexes bearing sterically bulky tridentate N,N′,N′′-trisubstituted tacn 2 to square pyramidal bis(µ-oxo)dicopper(III) complexes has been reported by Tolman et al. 3 In certain instances, they have observed a monooxygenase activity of the bis(µ-oxo)dicopper(III) complexes for the coordinated ligand as substrate. A different type of square planar bis(µ-oxo)dicopper(III) complexes having peralkylated-1,2-cyclohexanediamine ligands have been also prepared by Stack et al. 4 Very recently, partial formation of a bis(µ-oxo)dicopper(III) complex with a tridentate ligand containing two pyridyl sidearms 5 and a bis(µ-oxo)dicopper(III) complex with a bidentate ligand containing a pyridyl group have been reported. 6 However, there is no crystallographically characterized bis(µ-oxo)dicopper(III) complex having aromatic nitrogen donors. Thus, it is important to explore how the nature of the donor atoms and the stereochemistry of supporting ligands influence the formation, structure, and reactivity of bis(µ-oxo)dicopper(III) complexes.Karlin et al. have demonstrated that a copper(I) complex having a tetradentate tripodal tpa ligand, [Cu(tpa)(NCCH 3 )] + , reacts with O 2 to form a trans-(µ-1,2-peroxo)dicopper(II) complex ([Cu 2 (O 2 )-(tpa) 2 ] 2+ ) in a trigonal bipyramidal structure (λ max ( , M -1 cm -1 ) ) ∼440 nm (4000), 525 nm (11500), and ∼590 nm (7600)). 7 Previously we found that [Cu(Me-tpa)] + in acetone at -70 °C generates a trans-(µ-1,2-peroxo)dicopper(II) species, whereas the reaction of [Cu(Me 2 -tpa)] + (1a) with O 2 (Cu:O 2 ) 2:1) in acetone at -70 °C does not form a trans-(µ-1,2-peroxo)dicopper(II) species, but produces a brown species (1b, λ max ( , M -1 cm -1 ) ) 378 nm ( ∼22 000, 0.1 mM), 494 nm (330, 10 mM)). 8 Thus,
Inhibition of whole-cell calcium currents in enzymatically dispersed frog atrial myocytes by D-600, diltiazem, and nifedipine was studied using a single-micropipette voltage-clamp technique. The objective of these experiments was to test the applicability of a modulated-receptor hypothesis similar to that proposed for local anesthetic interactions with sodium channels to account for the tonic and frequency-dependent interactions of these organic compounds with myocardial calcium channels . Data consistent with such a hypothesis include: (a) prominent use-dependent block of ica by D-600 and diltiazem, which are predominantly charged at physiological pH; (b) ica block by an externally applied, permanently charged dihydropyridine derivative is greatly attenuated ; (c) all three antagonists produce large negative shifts in the voltage dependence of " availability ; (d) block of ic, by these compounds is state-dependent ; (e) reactivation of ica in the presence of all three antagonists is biexponential, which suggests that drug-free channels recover with a normal time course and drug-bound channels recover more slowly ; and (f) the kinetics of the drug-induced slow iCa recovery process may be determined largely by factors such as size and molecular weight, in addition to lipid solubility of the compounds. Experiments in which the pH was modified, however, reveal some important differences for the interaction of organic calcium antagonists with myocardial calcium channels . Acidification, in addition to changing the proportion of charged and neutral antagonist in solution, was found to selectively antagonize tonic inhibition of ica by diltiazem and nifedipine, without changing the kinetics of the drug-induced slow ica reactivation process. It is concluded that two distinct receptor sites may be involved in block of ica by some of these compounds: a proton-accessible site and a proton-inaccessible site .
A six-coordinate bis(μ-oxo)nickel(III) complex, [Ni2(μ-O)2(Me3-tpa)2]2+ (1), was synthesized by the reaction of [Ni2(μ-OH)2(Me3-tpa)2]2+ (2) with 1 equiv of hydrogen peroxide in methanol at −90 °C, where Me3-tpa = tris(6-methyl-2-pyridylmethyl)amine. The 6-methyl groups of Me3-tpa have a significant influence on the formation and stabilization of the high-valent bis(μ-oxo)dinickel(III) species. The reaction of 2 with a large excess of hydrogen peroxide (>10 equiv) afforded a novel bis(μ-superoxo)dinickel(II) complex, [Ni2(μ-O2)2(Me3-tpa)2]2+ (3), thus, the reaction demonstrates a unique conversion of a NiIII(μ-O)2NiIII core into a NiII(μ-OO)2NiII core upon exposure to hydrogen peroxide. Complexes 1, 2, and 3 have been characterized by X-ray crystallography and various physicochemical techniques. Complex 1 has a Ni(μ-O)2Ni core and the average Ni−O and Ni−N bond distances (1.871 and 2.143 Å, respectively) are significantly shorter than those of 2 (2.018 and 2.185 Å, respectively), suggesting that 1 is a bis(μ-oxo)dinickel(III) complex. Complex 3 consists of a Ni(μ-OO)2Ni core with two μ-1,2-O−O bridges to form a six-membered ring with chair conformation and the O−O bond distance is 1.345(6) Å. The resonance Raman spectrum of a powdered sample of 3 measured at ∼110 K showed an isotope-sensitive band at 1096 cm-1 (1044 cm-1 for an 18O-labeled sample), indicating that 3 is a bis(μ-superoxo)dinickel(II) complex. Thermal decomposition of both 1 and 3 in acetone at −20 °C under N2 atmosphere resulted in partial hydroxylation of a methyl group of Me3-tpa in yields of 21−27% for both complexes. For complex 3, a carboxylate complex, [Ni(Me2-tpaCOO)(OH2)]+ (4), where one of the three methyl groups of Me3-tpa is oxidized to carboxylate, was also isolated as a decomposed product under N2 atmosphere. During the decomposition process of 3, dioxygen evolution was simultaneously observed. The electrospray ionization mass spectrometry (ESI-MS) of 3 revealed the formation of 1 during the decomposition process. These results suggest that one possible decomposition pathway of 3 is a disproportionation of two coordinated superoxides to dioxygen and peroxide followed by the O−O bond scission of peroxide to regenerate 1, which is responsible for the hydroxylation and the oxidation of the 6-methyl group of Me3-tpa.
SUMMARY1. Single myocardial cells were enzymatically dispersed from guinea-pig atria and ventricles. At 25 0C, atrial cell action potentials differed significantly from ventricular cell action potentials in duration (atrial = 141 ms, ventricular = 497 ms) and overshoot (atrial = + 36 mV, ventricular = +42 mV).2. (Hume & Giles, 1983), or larger tip diameter pipettes, with internal dialysis (Hamill, Marty, Neher, Sakmann & Sigworth, 1981).4. Two significant differences in background K+ conductance in single atrial and ventricular myocytes were observed: (i) the isochronal (5 s 8. The rate of decay of ica was examined in ventricular myocytes, in which both time-dependent outward current and inward-rectifying K+ current were blocked by intracellular loading of caesium. iCa decay was non-exponential and lasted as long as 400 ms at + 20 mV. The decay could be described as the sum of two exponentials, the time constants of which were both U-shaped functions of membrane potential.9. It is concluded that different properties of resting K+ channels contribute significantly to the different action potential configurations of single atrial and ventricular myocytes. The time course of the plateau of the ventricular action potential is importantly determined by both the rate of decay of ica at positive membrane potentials and activation of time-dependent outward current. In atrial cells, the amplitude of iCa may be shunted due to the absence of a negative slope conductance region in the background current-voltage relationship.
Hydropathy analysis predicts 11 transmembrane helices in the cardiac Na + /Ca 2+ exchanger. Using cysteine susceptibility analysis and epitope tagging, we here studied the membrane topology of the exchanger, in particular of the highly conserved internal K K-1 and K K-2 repeats. Unexpectedly, we found that the connecting loop in the K K-1 repeat forms a re-entrant membrane loop with both ends facing the extracellular side and one residue (Asn-125) being accessible from the inside and that the region containing the K K-2 repeat is mostly accessible from the cytoplasm. Together with other data, we propose that the exchanger may consist of nine transmembrane helices.z 1999 Federation of European Biochemical Societies.
The single-channel blocking kinetics of tetrodotoxin (TTX), saxitoxin (STX), and several STX derivatives were measured for various Na-channel subtypes incorporated into planar lipid bilayers in the presence of batrachotoxin. The subtypes studied include Na channels from rat skeletal muscle and rat brain, which have high affinity for TTX/STX, and Na channels from denervated rat skeletal muscle and canine heart, which have about 20-60-fold lower affinity for these toxins at 22 degrees C. The equilibrium dissociation constant of toxin binding is an exponential function of voltage (e-fold per 40 mV) in the range of -60 to +60 mV. This voltage dependence is similar for all channel subtypes and toxins, indicating that this property is a conserved feature of channel function for batrachotoxin-activated channels. The decrease in binding affinity for TTX and STX in low-affinity subtypes is due to a 3-9-fold decrease in the association rate constant and a 4-8-fold increase in the dissociation rate constant. For a series of STX derivatives, the association rate constant for toxin binding is approximately an exponential function of net toxin charge in membranes of neutral lipids, implying that there is a negative surface potential due to fixed negative charges in the vicinity of the toxin receptor. The magnitude of this surface potential (-35 to -43 mV at 0.2 M NaCl) is similar for both high- and low-affinity subtypes, suggesting that the lower association rate of toxin binding to toxin-insensitive subtypes is not due to decreased surface charge but rather to a slower protein conformational step. The increased rates of toxin dissociation from insensitive subtypes can be attributed to the loss of a few specific bonding interactions in the binding site such as loss of a hydrogen bond with the N-1 hydroxyl group of neosaxitoxin, which contributes about 1 kcal/mol of intrinsic binding energy.
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