high conductance
Recently Published Documents


TOTAL DOCUMENTS

331
(FIVE YEARS 35)

H-INDEX

54
(FIVE YEARS 5)

Author(s):  
Salvatore Nesci

The c subunits, which constitutes the c-ring apparatus of the F F -ATPase, could be the main components of the mitochondrial permeability transition pore (mPTP). The well-known modulator of the mPTP formation and opening is the cyclophilin D (CyPD), a peptidyl-prolyl cis- trans isomerase. On the loop, which connects the two hairpin α-helix of c subunit, is present the unique proline residue (Pro ) that could be a biological target of CyPD. Indeed, the proline cis- trans isomerization might provide the switch that interconverts the open/closed states of the pore by pulling out the c-ring lipid plug.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Tobias Raisch ◽  
Andreas Brockmann ◽  
Ulrich Ebbinghaus-Kintscher ◽  
Jörg Freigang ◽  
Oliver Gutbrod ◽  
...  

AbstractSlowpoke (Slo) potassium channels display extraordinarily high conductance, are synergistically activated by a positive transmembrane potential and high intracellular Ca2+ concentrations and are important targets for insecticides and antiparasitic drugs. However, it is unknown how these compounds modulate ion translocation and whether there are insect-specific binding pockets. Here, we report structures of Drosophila Slo in the Ca2+-bound and Ca2+-free form and in complex with the fungal neurotoxin verruculogen and the anthelmintic drug emodepside. Whereas the architecture and gating mechanism of Slo channels are conserved, potential insect-specific binding pockets exist. Verruculogen inhibits K+ transport by blocking the Ca2+-induced activation signal and precludes K+ from entering the selectivity filter. Emodepside decreases the conductance by suboptimal K+ coordination and uncouples ion gating from Ca2+ and voltage sensing. Our results expand the mechanistic understanding of Slo regulation and lay the foundation for the rational design of regulators of Slo and other voltage-gated ion channels.


2021 ◽  
Author(s):  
Maria A Neginskaya ◽  
Sally E Morris ◽  
Evgeny V Pavlov

Mitochondrial permeability transition is caused by the opening of the Cyclosporin A (CSA) dependent calcium-induced large pore, known as the Permeability Transition Pore (PTP). PTP activation is believed to be a central event in stress-induced cell death. However, the molecular details of PTP opening remain incompletely understood. PTP opening makes mitochondrial inner membrane permeable to the molecules up to 1.5 kDa in size. Solute equilibration with the media in combination with swelling due to the PTP opening make mitochondria optically transparent, a phenomenon that has been widely used as a bona fide "light-scattering" PTP detection method in isolated mitochondria. Here, we utilized holographic microscopy imaging to monitor mitochondrial optical density changes that occur during solute equilibration between matrix and cytoplasm and thus enabled us to assess PTP induction in living cells. This approach relies on label-free, real-time mitochondrial visualization due to refractive index (RI) differences between the mitochondrial matrix and cytoplasm in the intact cells. PTP activation was detected as the decrease in mitochondrial RI. These measurements were done in parallel with measurements of the mitochondrial membrane potential, using the fluorescent probe TMRM. In intact HAP 1 cells, we found that calcium stress caused CSA-sensitive depolarization of the mitochondrial inner membrane. Unexpectedly, high-conductance PTP did not occur until after nearly complete mitochondrial membrane depolarization. In cells lacking c and δ subunits of the ATP synthase, we observed calcium-induced and CSA-sensitive depolarization but not high-conductance PTP. We demonstrate that holographic imaging is a powerful novel tool with unique capabilities that allow measurement of PTP in living cells with high temporal and spatial resolution. We conclude that contrary to the widely accepted view, in living cells, high-conductance PTP is not the cause of calcium-induced membrane depolarization. Further, we provide direct evidence that ATP synthase is essential for high-conductance PTP, but not for calcium-induced CSA-sensitive membrane depolarization. We propose that PTP activation occurs as a two-phase process, where the first phase of the initial membrane depolarization is followed by the second phase of large pore opening that results in high-amplitude membrane permeabilization.


Author(s):  
Laura Begon-Lours ◽  
Mattia Halter ◽  
Youri Popoff ◽  
Zhenming Yu ◽  
Donato Francesco Falcone ◽  
...  
Keyword(s):  

Author(s):  
Laura Begon-Lours ◽  
Mattia Halter ◽  
Youri Popoff ◽  
Zhenming Yu ◽  
Donato Francesco Falcone ◽  
...  
Keyword(s):  

2021 ◽  
Author(s):  
Robert A Rietmeijer ◽  
Em Sorum ◽  
Baobin Li ◽  
Stephen G. Brohawn

TRAAK is a mechanosensitive two-pore domain K+ (K2P) channel localized to nodes of Ranvier in myelinated neurons. TRAAK deletion in mice results in mechanical and thermal allodynia and gain-of-function mutations cause the human neurodevelopmental disorder FHEIG. TRAAK displays basal and stimulus-gated activities typical of K2Ps, but the mechanistic and structural differences between these modes are unknown. Here, we demonstrate that basal and mechanically-gated openings are distinguished by their conductance, kinetics, and structure. Basal openings are low conductance, short duration, and occur through a channel with an interior cavity exposed to the surrounding membrane. Mechanically-gated openings are high conductance, long duration, and occur through a channel that is sealed to the surrounding membrane. Our results explain how dual modes of activity are produced by a single ion channel and provide a basis for the development of state-selective pharmacology with the potential to treat disease.


2021 ◽  
Vol 2 (2) ◽  
pp. 1258-1265
Author(s):  
Marleni Reyes Monreal ◽  
Jessica Quintero Pérez ◽  
Miguel Pérez Escalera ◽  
Arturo Reyes Lazalde ◽  
María Eugenia Pérez Bonilla

The presence, in the cell membrane, of high-conductance K+ channels and voltage-gated Ca2+ channels (CaV) forming complexes has been reported. These complexes have important functions in excitable cells. The [Ca2+]i at the mouth of the CaV channel decreases with distance and with the concentration of chelators. For the BK channel to be activated with internal Ca2, a concentration of the order of M is necessary and this implies a closeness between the BK-CaV channels. A simulator of the decay of Ca2+ in the presence of BAPTA to estimate the distance between the channels was developed. The mathematical models were implemented in Visual Basic® 6.0 and were solved numerically. The results indicate the coexistence of L-type CaV channel and BK grouped in nanodomains with a distance between channels of ~30 nm.


2021 ◽  
Vol 2 (2) ◽  
pp. 1241-1257
Author(s):  
Marleni Reyes Monreal ◽  
Jessica Quintero Pérez ◽  
Miguel Felipe Pérez Escalera ◽  
Arturo Reyes Lazalde ◽  
María Eugenia Pérez Bonilla

Complexes formed by voltage-activated calcium channels (CaV) and high-conductance potassium channels activated by Ca2+ (BK) have been studied in smooth muscle, secretory cells and in synaptic terminals, where they regulate muscle contraction, secretory activity, and neurotransmission. However, the complex formed by L- type CaV channels and BK in the soma has been poorly treated. Based on immunostaining studies showing the coexistence of these channels in the neuron soma, their possible interaction was theoretically studied. Two simulators based on the Hodgkin and Huxley formalism were developed to perform virtual experiments on current and voltage clamp. The mathematical models were implemented in Visual Basic® 6.0 and were solved numerically. The results indicate that the BK channels were activated with internal Ca2+ at mM concentrations. The BK channels follow the kinetics of L-type CaVs. The interaction of L-type CaV – BK complex in the soma produced a decrease in neuronal excitability.


Sign in / Sign up

Export Citation Format

Share Document