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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Mechanosensing and Symmetry of Potassium Channels Studied by Molecular Dynamics Simulations

Brennecke, Julian Tim 02 October 2018 (has links)
No description available.
2

A study of ultrasound neuromodulation mechanisms using crayfish motor axons

Yu, Feiyuan 08 February 2024 (has links)
Focused ultrasound (FUS) mediated neuromodulation has become a trending topic due to its promising attributes that enable precise and transcranial neuromodulation. Despite multiple reports of FUS effects on neurons, nervous systems, and the human brain, the mechanisms underlying such excitation or inhibition remain controversial. In our previous study, we showed that 2.1 MHz FUS induced membrane depolarizations on single crayfish motor axons in the presence of voltage-gated channel blockers, which led to a nanopore hypothesis: FUS triggered lipid molecule reconfiguration and form ion-permeable nanopores on the axonal membrane. Based on this hypothesis, stretching of the axonal membrane due to swelling in low osmolarity should increase the probability of nanopore formation under FUS. As predicted, exposure to 75% hypotonic saline induced significant increases in amplitude and frequency of occurrence of those FUS-induced depolarizations (FUSD) while the onset latency of the FUSD showed a significant decrease. Those results support the hypothesis that FUSD can be modulated by mechanically altering membrane properties. Since FUS inevitably perturbs cell membranes, we examined the role of mechanosensitive K2P channels at the crayfish opener neuromuscular junction. At ultrasound intensity lower than those used to evoke FUSD, FUS consistently induced membrane hyperpolarization (FUSH) in motor axons but not muscle fibers, which may lack K2P. Since K2P channels are also thermosensitive, we varied the temperature from 12 to 32 °C. However, there was no significant correlation between FUSH amplitudes and temperature. Furthermore, FUSH was not inhibited by the K2P channel blockers, although the presence of the channels was confirmed by K2P blockers which increased input resistance and depolarized axonal resting membrane potential. Thus, it is unlikely that K2P channels underlie FUSH. We also studied the impact of FUS on propagating action potentials (APs) in the crayfish motor axons. APs recorded during FUS took off from a hyperpolarized membrane potential and exhibited larger amplitudes and shorter duration. Three hypotheses were examined and eliminated. The US modulated AP shape changes cannot be due to: (1) alterations in microelectrode characteristics, (2) the increase in the fraction of sodium channels in the closed and not-inactivated state due to the hyperpolarization and (3) US activation of K2P channels which in turn altered AP shapes. One potential mechanism that requires further investigation is that FUS may accelerate the activation of sodium channel opening. Other factors that may indirectly modulate AP shapes are discussed. In summary, results presented in this thesis suggest that FUS-mediated membrane responses in a single cell could vary depending on the FUS intensity and the type of ion channel a given cell expresses. Furthermore, ultrasound not only evokes changes membrane potential but also modulates action potentials. Collectively, these results represent significant contribution to the understanding of mechanisms underlying ultrasound neuromodulation at the cellular level.
3

Pharmacological Modulation Of Recombinant Human Two-Pore Domain K+ Channels : Whole-Cell patch-Clamp Analysis

Harinath, S 10 1900 (has links) (PDF)
Background potassium currents play an important role in the regulation of the resting membrane potential and excitability of mammalian neurons. Recently cloned two- pore domain potassium channels (K2p) are believed to underlie these currents. The roles of K2P channels in general anesthesia and neuroprotection have been proposed recently. In view of this, we investigated the ability of trichloroethanol (an active metabolite of the non-volatile general anesthetic cldoral hydrate, widely used as a pediatric sedative) to modulate the activity of human TREK-1 and TRAAK channels. We found that trichloroethanol potently activates both hTREK-1 and hTRAAK channels at pharmacologically relevant concentrations. The parent compound chloral hydrate was also found to augtnent the activity of both the channels reversibly. Studies with carboxy- terminal deletion mutants (hTREK-1A89, hTREK-1 A100 and hTREK-1 A1 19), suggested that C-terminal tail is not essential for the activation of TREK-1 by trichloroethanol. Our findings identify TREK-1 and TRCL4K channels as molecular targets for trichloroethanol and we propose that activation of both these channels might contribute to the CNS depressant effects of chloral hydrate. Another channel TASK-2, which is essentially absent in the human brain was also found to be potently activated by both trichloroethanol and chloral hydrate. In another series of experiments, we studied the effects of methyl xanthines caffeine and theophylline on hTREK-1 channels. Caffeine and theophylline are used for therapeutic purposes and frequently cause life-threatening convulsive seizures due to systemic toxicity. The mechanisms for the epileptogenicity of caffeine and theophylline are not clear. Recent experiments using knockout mice provided direct evidence for a role for TREK-1 in the control of epileptogenesis. We hypothesized that the epileptogenicity of caffeine and theophylline may be related to the inhibition of TREK-1 channels. We investigated this possibility and observed massive inhibition of TREK-1 channels at toxicologically relevant concentrations. Experiments with the mutant TREK-1 channel (S348A mutant) suggested the involvement of cANP/PKA pathway in the inhibition of TREK-1 channels by caffeine and theophylline. We suggest that inhibition of TREK-1 channels may contribute to the convulsive seizures induced by toxic levels of caffeine and theophylline. Local anesthetics exhibit their clinical effects not only by binding to voltage-gated sodium channels, but also by interacting with other ion channels such as potassium channels. Because of the physiological significance of TREK-1 channels and their abundant expression in peripheral sensory neurons, we investigated the effects of lidocaine to see whether its interaction with 'REK-1 channels contribute to the conduction blockade. Lidocaine caused dose-dependent inhibition of TREK-1channels and the inhibition was voltage-independent. Cytoplasmic C-terminal tail is critically required for lidocaine action. Inhibition of TREK-1 channels is achieved at concentrations for iiz vivo action and this effect may have implications for the clinically observed drug action of lidocaine.

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