Mechanotransducing ion channels in astrocytes

Bowman, Charles L.; Ding, Jiuping; Sachs, Frederick; Sokabe, Masahiro

doi:10.1016/0006-8993(92)90906-p

Cited by 88 publications

(42 citation statements)

References 33 publications

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“…8B; k 34 1 ϭ 0.06͞mmHg) reflects an equal decrease in channel area, so that the dimensions of the desensitized state would be about the same size as the resting state. The numeric values apply, in detail, only to this data set.…”

Section: Resultsmentioning

confidence: 99%

“…Excision commonly causes a rundown of mechanosensitive channels (5,26,34), but K 2P channels undergo ''run up'' (Figs. 1 A and B and 2 A; see also refs.…”

Section: Resultsmentioning

confidence: 99%

“…(B) The kinetic model used to fit the data illustrated in A (same conventions). The preexponential constants and the pressure sensitivities of k 12 and k23 were arbitrarily constrained to be equal, as were the rates k 34 and k41, and k32 and k 21. (C) TRAAK channel currents in an inside-out patch with a global fit (in red) to the data set by using a model similar to B.…”

Section: Resultsmentioning

confidence: 99%

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Desensitization of mechano-gated K _2P channels

Honoré

Patel

Chemin

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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129

115

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The neuronal mechano-gated K2P channels TREK-1 and TRAAK show pronounced desensitization within 100 ms of membrane stretch. Desensitization persists in the presence of cytoskeleton disrupting agents, upon patch excision, and when channels are expressed in membrane blebs. Mechanosensitive currents evoked with a variety of complex stimulus protocols were globally fit to a four-state cyclic kinetic model in detailed balance, without the need to introduce adaptation of the stimulus. However, we show that patch stress can be a complex function of time and stimulation history. The kinetic model couples desensitization to activation, so that gentle conditioning stimuli do not cause desensitization. Prestressing the channels with pressure, amphipaths, intracellular acidosis, or the E306A mutation reduces the peak-to-steady-state ratio by changing the preexponential terms of the rate constants, increasing the steady-state current amplitude. The mechanical responsivity can be accounted for by a change of in-plane area of Ϸ2 nm 2 between the closed and open conformations. Desensitization and its regulation by chemical messengers is predicted to condition the physiological role of K2P channels.M ost receptors, including ligand-gated ion channels, desensitize with continuous stimulation. Desensitization is a reversible, use-dependent, form of signal plasticity critical for maintaining the dynamic sensitivity over a wide dynamic range. Desensitization also protects cells from inappropriate persistent activation. Many mechano-gated ion channels desensitize (1-5). There are two basic mechanisms that account for desensitization: adaptation and inactivation. Adaptation refers to the uncoupling of the stimulus from the channel, whereas inactivation refers to a block of the permeation path. In hair cells of the inner ear, deflection opens a mechano-gated channel at the tip of the stereocilium leading to depolarization (6). A fast adaptation mechanism (0.3-5 ms) is attributed to the binding of calcium near the channel after permeation through the open ionic pore (6), i.e., Ca 2ϩ block. A slower adaptation (10-100 ms) occurs when the calcium-dependent molecular motor myosin-1c, which pulls on the channels, slips down the actin cytoskeleton reducing the force applied to the channel (6).Rapid desensitization also occurs in mechanosensitive channels expressed in nonspecialized cells. For instance, the stretchactivated cation channel of Xenopus oocyte opens transiently in response to a step change in patch pressure (5). The decrease in current has been attributed to relaxation of the mechanical stimulus, although as shown in this work, that interpretation may not be a good discriminator. Desensitization of the oocyte channel is fragile and may disappear when patches are repetitively stimulated (5). This fragility was attributed to decoupling of the bilayer from the cytoskeleton (5).Stretch-activated K ϩ channels are present in neurons of both the central and the peripheral nervous systems (7-9), and they also have been described in nonne...

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Section: Resultsmentioning

confidence: 99%

“…Excision commonly causes a rundown of mechanosensitive channels (5,26,34), but K 2P channels undergo ''run up'' (Figs. 1 A and B and 2 A; see also refs.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Desensitization of mechano-gated K _2P channels

Honoré

Patel

Chemin

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

129

115

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“…For instance, direct strain to astrocytes has been shown to increase cytosolic calcium from both extracellular and intracellular sources, which increased with more severe insults; however, these experiments did not independently isolate the effects of strain and strain rate (Rzigalinski et al, 1998;Floyd et al, 2001;Neary et al, 2003). Additionally, mechanical stress may open stretch-activated ion channels, leading to increased intracellular calcium (Bowman et al, 1992;Rzigalinski et al, 1998;Floyd et al, 2005). Thus, astrocytes may possess mechanisms to directly respond to mechanical stress and the associated deformation in both physiological and pathophysiological settings.…”

Section: Introductionmentioning

confidence: 96%

“…In vitro models offer a high degree of experimental control, providing the ability to impart defined mechanical inputs and assess the resulting cellular alterations. Direct strain transfer to astrocytes may be an initiating factor for astrogliotic alterations via mechanosensation or mechanotransduction, the process by which cells convert mechanical stimuli into changes in intracellular biochemical signaling (Guharay and Sachs, 1984;Bowman et al, 1992;Ingber, 1997;Alenghat and Ingber, 2002;Kamm and Kaazempur-Mofrad, 2004). Mechanosensitive elements may directly affect ion homeostasis in astrocytes.…”

Section: Introductionmentioning

confidence: 99%

Strain rate-dependent induction of reactive astrogliosis and cell death in three-dimensional neuronal–astrocytic co-cultures

2007

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A mechanical insult to the brain drastically alters the microenvironment as specific cell types become reactive in an effort to sequester severely damaged tissue. Although injury-induced astrogliosis has been investigated, the relationship between well-defined biomechanical inputs and acute astrogliotic alterations are not well understood. We evaluated the effects of strain rate on cell death and astrogliosis using a three-dimensional (3-D) in vitro model of neurons and astrocytes within a bioactive matrix. At 21 days post-plating, co-cultures were deformed to 0.50 shear strain at strain rates of 1, 10, or 30 s −1 . We found that cell death and astrogliotic profiles varied differentially based on strain rate at two days post-insult. Significant cell death was observed after moderate (10 s −1 ) and high (30 s −1 ) rate deformation, but not after quasi-static (1 s −1 ) loading. The vast majority of cell death occurred in neurons, suggesting these cells are more susceptible to high rate shear strains than astrocytes for the insult parameters used here. Injury-induced astrogliosis was compared to co-cultures treated with transforming growth factor β, which induced robust astrocyte hypertrophy and increased glial fibrillary acidic protein (GFAP) and chondroitinsulfate proteoglycans (CSPGs). Quasi-static loading resulted in increased cell density and CSPG secretion. Moderate rate deformation increased cell density, GFAP reactivity, and hypertrophic process density. High rate deformation resulted in increased GFAP reactivity; however, other astrogliotic alterations were not observed at this time-point. These results demonstrate that the mode and degree of astrogliosis depend on rate of deformation, demonstrating astrogliotic augmentation at sub-lethal injury levels as well as levels inducing cell death.

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