571 research outputs found
MECHANISMS OF DISEASE Acute Oxygen-Sensing Mechanisms
JOSEPH PRIESTLEY, ONE OF THE THREE SCIENTISTS CREDITED WITH THE discovery of oxygen, described the death of mice that were deprived of oxygen. However, he was also well aware of the toxicity of too much oxygen, stating, âFor as a candle burns much faster in dephlogisticated [oxygen enriched] than in common air, so we might live out too fast, and the animal powers be too soon exhausted in this pure kind of air. A moralist, at least, may
say, that the air which nature has provided for us is as good as we deserve.â1
In this review we examine the remarkable mechanisms by which different organs detect and respond to acute changes in oxygen tension. Specialized tissues that sense the local oxygen tension include glomus cells of the carotid body, neuroepithelial bodies in the lungs, chromaffin cells of the fetal adrenal medulla, and smooth-muscle cells of the resistance pulmonary arteries,
fetoplacental arteries, systemic arteries, and the ductus arteriosus. Together, they constitute a specialized homeostatic oxygen-sensing system. Although all tissues are sensitive to severe hypoxia, these specialized tissues respond rapidly to moderate changes in oxygen tension within the physiologic range (roughly 40 to 100 mm Hg in an adult and 20 to 40 mm Hg in a fetus)Junta de AndalucĂ
Carotid body chemosensory responses in mice deficient of TASK channels
Background K+ channels of the TASK family are believed to participate in sensory transduction by chemoreceptor (glomus) cells of the carotid body (CB). However, studies on the systemic CB-mediated ventilatory response to hypoxia and hypercapnia in TASK1- and/or TASK3-deficient mice have yielded conflicting results. We have characterized the glomus cell phenotype of TASK-null mice and studied the responses of individual cells to hypoxia and other chemical stimuli. CB morphology and glomus cell size were normal in wild-type as well as in TASK1â/â or double TASK1/3â/â mice. Patch-clamped TASK1/3-null glomus cells had significantly higher membrane resistance and less hyperpolarized resting potential than their wild-type counterpart. These electrical parameters were practically normal in TASK1â/â cells. Sensitivity of background currents to changes of extracellular pH was drastically diminished in TASK1/3-null cells. In contrast with these observations, responsiveness to hypoxia or hypercapnia of either TASK1â/â or double TASK1/3â/â cells, as estimated by the amperometric measurement of catecholamine release, was apparently normal. TASK1/3 knockout cells showed an enhanced secretory rate in basal (normoxic) conditions compatible with their increased excitability. Responsiveness to hypoxia of TASK1/3-null cells was maintained after pharmacological blockade of maxi-K+ channels. These data in the TASK-null mouse model indicate that TASK3 channels contribute to the background K+ current in glomus cells and to their sensitivity to external pH. They also suggest that, although TASK1 channels might be dispensable for O2/CO2 sensing in mouse CB cells, TASK3 channels (or TASK1/3 heteromers) could mediate hypoxic depolarization of normal glomus cells. The ability of TASK1/3â/â glomus cells to maintain a powerful response to hypoxia even after blockade of maxi-K+ channels, suggests the existence of multiple sensor and/or effector mechanisms, which could confer upon the cells a high adaptability to maintain their chemosensory function
An electrostatic interaction between TEA and an introduced pore aromatic drives spring-in-the-door inactivation in Shaker potassium channels
Slow inactivation of Kv1 channels involves conformational changes near the selectivity filter. We examine such changes in Shaker channels lacking fast inactivation by considering the consequences of mutating two residues, T449 just external to the selectivity filter and V438 in the pore helix near the bottom of the selectivity filter. Single mutant T449F channels with the native V438 inactivate very slowly, and the canonical foot-in-the-door effect of extracellular tetraethylammonium (TEA) is not only absent, but the time course of slow inactivation is accelerated by TEA. The V438A mutation dramatically speeds inactivation in T449F channels, and TEA slows inactivation exactly as predicted by the foot-in-the-door model. We propose that TEA has this effect on V438A/T449F channels because the V438A mutation produces allosteric consequences within the selectivity filter and may reorient the aromatic ring at position 449. We investigated the possibility that the blocker promotes the collapse of the outer vestibule (spring-in-the-door) in single mutant T449F channels by an electrostatic attraction between a cationic TEA and the quadrupole moments of the four aromatic rings. To test this idea, we used in vivo nonsense suppression to serially fluorinate the introduced aromatic ring at the 449 position, a manipulation that withdraws electrons from the aromatic face with little effect on the shape, net charge, or hydrophobicity of the aromatic ring. Progressive fluorination causes monotonically enhanced rates of inactivation. In further agreement with our working hypothesis, increasing fluorination of the aromatic gradually transforms the TEA effect from spring-in-the-door to foot-in-the-door. We further substantiate our electrostatic hypothesis by quantum mechanical calculations
Unexpected obesity, rather than tumorigenesis, in a conditional mouse model of mitochondrial complex II deficiency
Mutations in any of the genes encoding the four subunits of succinate dehydrogenase (SDH), a mitochondrial membrane-bound enzyme complex that is involved in both the tricarboxylic acid cycle and the electron transport chain, can lead to a variety of disorders. Recognized conditions with such mutations include Leigh syndrome and hereditary tumors such as pheochromocytoma and paraganglioma (PPGL), renal cell carcinoma, and gastrointestinal stromal tumor. Tumors appear in SDH mutation carriers with dominant inheritance due to loss of heterozygosity in susceptible cells. Here, we describe a mouse model intended to reproduce hereditary PPGL through Cre-mediated loss of SDHC in cells that express tyrosine hydroxylase (TH), a com-partment where PPGL is known to originate. We report that while there is modest expansion of TH+ glomus cells in the carotid body upon SDHC loss, PPGL is not observed in such mice, even in the presence of a conditional dominant negative p53 protein and chronic hypoxia. Instead, we report an unexpected phenotype of nondia-betic obesity beginning at about 20 weeks of age. We hypothesize that this obesity is caused by TH+ cell loss or altered phenotype in key compartments of the central nervous system responsible for regulating feeding behavior, coupled with metabolic changes due to loss of peripheral catecholamine production.Spanish Ministries of Science and Innovation and HealthEuropean Research Counci
Faddeev Calculations of Proton-Deuteron Radiative Capture with Exchange Currents
pd capture processes at various energies have been analyzed based on
solutions of 3N-Faddeev equations and using modern NN forces. The application
of the Siegert theorem is compared to the explicit use of - and
-like exchange currents connected to the AV18 NN interaction. Overall
good agreement with cross sections and spin observables has been obtained but
leaving room for improvement in some cases. Feasibility studies for 3NF's
consistently included in the 3N continuum and the 3N bound state have been
performed as well.Comment: Minor changes in notation, ps files for figure
Measurement of the LT-asymmetry in \pi^0 electroproduction at the energy of the \Delta (1232) resonance
The reaction p(e,e'p)pi^0 has been studied at Q^2=0.2 (GeV/c)^2 in the region
of W=1232 MeV. From measurements left and right of q, cross section asymmetries
\rho_LT have been obtained in forward kinematics \rho_LT(\theta_\pi^0=20deg) =
(-11.68 +/- 2.36_stat +/- 2.36_sys)$ and backward kinematics
\rho_LT(\theta_\pi^0=160deg) =(12.18 +/- 0.27_stat +/- 0.82_sys). Multipole
ratios \Re(S_1+^* M_1+)/|M_1+|^2 and \Re(S_0+^* M_1+)/|M_1+|^2 were determined
in the framework of the MAID2003 model. The results are in agreement with older
data. The unusally strong negative \Re(S_0+^* M_1+)/|M_1+|^2 required to bring
also the result of Kalleicher et al. in accordance with the rest of the data is
almost excluded.Comment: 7 pages, 7 figures, 4 tables. Changed content. Accepted for
publication in EPJ
The selectivity, voltage-dependence and acid sensitivity of the tandem pore potassium channel TASK-1 : contributions of the pore domains
We have investigated the contribution to ionic
selectivity of residues in the selectivity filter and pore
helices of the P1 and P2 domains in the acid sensitive
potassium channel TASK-1. We used site directed mutagenesis
and electrophysiological studies, assisted by structural
models built through computational methods. We have
measured selectivity in channels expressed in Xenopus
oocytes, using voltage clamp to measure shifts in reversal
potential and current amplitudes when Rb+ or Na+ replaced
extracellular K+. Both P1 and P2 contribute to selectivity,
and most mutations, including mutation of residues in the
triplets GYG and GFG in P1 and P2, made channels nonselective.
We interpret the effects of theseâand of other
mutationsâin terms of the way the pore is likely to be
stabilised structurally. We show also that residues in the
outer pore mouth contribute to selectivity in TASK-1.
Mutations resulting in loss of selectivity (e.g. I94S, G95A)
were associated with slowing of the response of channels to
depolarisation. More important physiologically, pH sensitivity
is also lost or altered by such mutations. Mutations
that retained selectivity (e.g. I94L, I94V) also retained their
response to acidification. It is likely that responses both to
voltage and pH changes involve gating at the selectivity filter
First measurements of the ^16O(e,e'pn)^14N reaction
This paper reports on the first measurement of the ^16O(e,e'pn)^14N reaction.
Data were measured in kinematics centred on a super-parallel geometry at energy
and momentum transfers of 215 MeV and 316 MeV/c. The experimental resolution
was sufficient to distinguish groups of states in the residual nucleus but not
good enough to separate individual states. The data show a strong dependence on
missing momentum and this dependence appears to be different for two groups of
states in the residual nucleus. Theoretical calculations of the reaction using
the Pavia code do not reproduce the shape or the magnitude of the data.Comment: 10 pages, 11 figures, 2 tables, Accepted for publication in EPJ
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