scholarly journals Pathways for nicotinic receptor desensitization

2020 ◽  
Vol 152 (10) ◽  
Author(s):  
Anthony Auerbach
Keyword(s):  
Transition State ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Open Channel ◽  
Energy Surface ◽  
Surface Model ◽  
Closed Channel ◽  
Discrete State ◽  
State Region ◽  
Selection Of

Nicotinic acetylcholine receptors (AChRs) are ligand-gated ion channels that generate transient currents by binding agonists and switching rapidly between closed- and open-channel conformations. Upon sustained exposure to ACh, the cell response diminishes slowly because of desensitization, a process that shuts the channel even with agonists still bound. In liganded receptors, the main desensitization pathway is from the open-channel conformation, but after agonists dissociate the main recovery pathway is to the closed-channel conformation. In this Viewpoint, I discuss two mechanisms that can explain the selection of different pathways, a question that has puzzled the community for 60 yr. The first is based on a discrete-state model (the “prism”), in which closed, open, and desensitized conformational states interconnect directly. This model predicts that 5% of unliganded AChRs are desensitized. Different pathways are taken with versus without agonists because ligands have different energy properties (φ values) at the transition states of the desensitization and recovery reactions. The second is a potential energy surface model (the “monkey saddle”), in which the states connect indirectly at a shared transition state region. Different pathways are taken because agonists shift the position of the gating transition state relative to the point where gating and desensitization conformational trajectories intersect. Understanding desensitization pathways appears to be a problem of kinetics rather than of thermodynamics. Other aspects of the two mechanisms are considered, as are experiments that may someday distinguish them.

scholarly journals Mechanism of Tacrine Block at Adult Human Muscle Nicotinic Acetylcholine Receptors

2002 ◽  
Vol 120 (3) ◽  
pp. 369-393 ◽  
Author(s):  
Richard J. Prince ◽  
Richard A. Pennington ◽  
Steven M. Sine
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Binding Sites ◽  
Acetylcholine Receptors ◽  
Open Channel ◽  
Single Channel ◽  
Dependent Manner ◽  
Open Probability ◽  
Sequential Model ◽  
Hek 293 ◽  
Voltage Dependent

We used single-channel kinetic analysis to study the inhibitory effects of tacrine on human adult nicotinic receptors (nAChRs) transiently expressed in HEK 293 cells. Single channel recording from cell-attached patches revealed concentration- and voltage-dependent decreases in mean channel open probability produced by tacrine (IC50 4.6 μM at −70 mV, 1.6 μM at −150 mV). Two main effects of tacrine were apparent in the open- and closed-time distributions. First, the mean channel open time decreased with increasing tacrine concentration in a voltage-dependent manner, strongly suggesting that tacrine acts as an open-channel blocker. Second, tacrine produced a new class of closings whose duration increased with increasing tacrine concentration. Concentration dependence of closed-times is not predicted by sequential models of channel block, suggesting that tacrine blocks the nAChR by an unusual mechanism. To probe tacrine's mechanism of action we fitted a series of kinetic models to our data using maximum likelihood techniques. Models incorporating two tacrine binding sites in the open receptor channel gave dramatically improved fits to our data compared with the classic sequential model, which contains one site. Improved fits relative to the sequential model were also obtained with schemes incorporating a binding site in the closed channel, but only if it is assumed that the channel cannot gate with tacrine bound. Overall, the best description of our data was obtained with a model that combined two binding sites in the open channel with a single site in the closed state of the receptor.

scholarly journals Sampling the Folding Transition State Ensemble in a Tube-Like Model of Protein

10.29007/ml3c ◽  
2020 ◽  
Author(s):  
Ba Hung Nguyen ◽  
Hoang Trinh Xuan
Keyword(s):  
Free Energy ◽  
Transition State ◽  
Energy Surface ◽  
Sampling Technique ◽  
Small Region ◽  
Umbrella Sampling ◽  
Free Energy Surface ◽  
State Ensemble ◽  
State Region ◽  
Transition State Ensemble

We used the tube model with Go-like potential for native contacts to study the folding transition of a designed three-helix bundle and a designed protein G-like structure. It is shown that both proteins in this model are two-state folders with a cooperative folding transition coincided with the collapse transition. We defined the transition states as protein conformations in a small region around the saddle point on a free energy surface with the energy and the conformational root-mean-square deviation (RMSD) from the native state as the coordinates. The transition state region on the free energy surface then was sampled by using the umbrella sampling technique. We show that the transition state ensemble is broad consisting of different conformations that have different folded and unfolded elements.

Calcium Flux Through Predominantly Independent Purinergic ATP and Nicotinic Acetylcholine Receptors

1997 ◽  
Vol 77 (3) ◽  
pp. 1407-1417 ◽  
Author(s):  
Marc Rogers ◽  
Lorna M. Colquhoun ◽  
James W. Patrick ◽  
John A. Dani
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Open Channel ◽  
Sympathetic Neurons ◽  
Cross Reactivity ◽  
Calcium Flux ◽  
Nicotinic Acetylcholine ◽  
Atp Receptors ◽  
Intracellular Signals ◽  
Activity Dependent

Rogers, Marc, Lorna M. Colquhoun, James W. Patrick, and John A. Dani. Calcium flux through predominantly independent purinergic ATP and nicotinic acetylcholine receptors. J. Neurophysiol. 77: 1407–1417, 1997. Ligand-gated nicotinic acetylcholine receptors (nAChRs) and purinergic ATP receptors are often expressed in the same peripheral and central neurons, and ATP and acetylcholine (ACh) are stored together in some synaptic vesicles. Evidence has suggested that nAChRs and ATP receptors are not independent and that some agonists strongly cross-activate and desensitize both receptor types. Rat sympathetic neurons and nAChRs expressed in Xenopus oocytes were studied to determine the significance of the interactions caused by the two agonist types. Current amplitudes induced with separate or combined applications of ATP and nicotine are >90% additive and independent. Half of all neurons tested responded to either ATP or nicotine but not to both, indicating differences in the expression of the two receptors. In neurons that expressed both receptor types, the nAChRs were inhibited by the activity-dependent open-channel blocker chlorisondamine. If the purinergic and nicotinic receptors were significantly dependent and coactivated, then blocking the ion channels opened by a nicotinic agonist should diminish the current activated by a purinergic agonist. That result was not seen; rather, complete open-channel block of nAChRs with chlorisondamine did not significantly alter the amplitude or kinetics of ATP-induced currents in the same neurons. Finally, when cloned nAChR subunits were expressed in oocytes, ATP activated only very small currents compared with the current activated by ACh. For the 13 different nAChR subunit combinations that were studied, ATP (50–500 μM) activated a current that ranged from 0 to 4% of the size of the current activated by 100 μM ACh. In summary, we find that there is little cross reactivity, and nAChRs and purinergic ATP receptors are predominately independent, acting with separable physiological characteristics. Therefore the quantitative Ca2+ flux could be separately determined for nAChRs and ATP receptors. The fraction of total current that is carried by Ca2+ was quantitatively determined by simultaneously measuring the whole cell current and the associated change in intracellular Ca2+ with fura-2. For sympathetic neurons bathed in 2.5 mM Ca2+ at a holding potential of −50 mV, Ca2+ carries 4.8 ± 0.3% (mean ± SE) of the inward current through neuronal nAChRs and 6.5 ± 0.1% of the current through purinergic ATP receptors. In conclusion, activity-dependent Ca2+ influx through predominately independent populations of nAChRs and ATP receptors can produce different intracellular signals at purinergic and cholinergic synapses.

scholarly journals Sampling the Folding Transition State Ensemble in a Tube-like Model of Protein

2019 ◽  
Vol 29 (2) ◽  
pp. 129
Author(s):  
Nguyen Ba Hung ◽  
Trinh Xuan Hoang
Keyword(s):  
Free Energy ◽  
Transition State ◽  
Energy Surface ◽  
Sampling Technique ◽  
Small Region ◽  
Umbrella Sampling ◽  
Free Energy Surface ◽  
State Ensemble ◽  
State Region ◽  
Transition State Ensemble

We used the tube model with Go-like potential for native contacts to study the folding transition of a designed three-helix bundle and a designed protein G-like structure. It is shown that both proteins in this model are two-state folders with a cooperative folding transition coincided with the collapse transition. We defined the transition states as protein conformations in a small region around the saddle point on a free energy surface with the energy and the conformationalroot mean square deviation (rmsd) from the native state as the coordinates. The transition state region on the free energy surface then was sampled by using umbrella sampling technique. We show that the transition state ensemble is broad consisting of different conformations that have different folded and unfolded elements.

Molecular mechanisms of open-channel blockade in nicotinic acetylcholine receptors of autonomic ganglia neurons

1992 ◽  
Vol 70 (S1) ◽  
pp. S78-S85 ◽  
Author(s):  
Vladimir I. Skok
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Open Channel ◽  
Ionic Channels ◽  
Channel Blockers ◽  
Autonomic Ganglia ◽  
Nicotinic Acetylcholine ◽  
Enteric Ganglia ◽  
Channel Blocking

The results of recent attempts to estimate the dimensions of ionic channels in nicotinic acetylcholine receptors of sympathetic and enteric ganglia neurons are reviewed. The channel dimensions, obtained from comparison of the sizes of the open-channel blocking molecules with their blocking activities, are 6.1 × 8.3 Å (1 Å = 0.1 nm) in both sympathetic and enteric ganglia. None of the competitive ganglionic blockers fit within this channel size. In addition, a chemical structure that binds the open-channel blockers in ganglionic nicotinic acetylcholine receptors is suggested to be formed by serine and threonine residues, as found by comparing the differences between the structures of the neuronal and muscle nicotinic acetylcholine receptors with the differences in their pharmacology.Key words: nicotinic acetylcholine receptor, autonomic ganglia, open-channel blocking mechanisms.

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