scholarly journals Mechanism of gating and partial agonist action in the glycine receptor

Cell ◽  
2021 ◽  
Vol 184 (4) ◽  
pp. 957-968.e21 ◽  
Author(s):  
Jie Yu ◽  
Hongtao Zhu ◽  
Remigijus Lape ◽  
Timo Greiner ◽  
Juan Du ◽  
...  
Keyword(s):  
Partial Agonist ◽  
Glycine Receptor ◽  
Agonist Action

scholarly journals Mechanism of gating and partial agonist action in the glycine receptor

2019 ◽  
Author(s):  
Jie Yu ◽  
Hongtao Zhu ◽  
Remigijus Lape ◽  
Timo Greiner ◽  
Rezvan Shahoei ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Molecular Mechanisms ◽  
Open Channel ◽  
Partial Agonist ◽  
Glycine Receptor ◽  
Md Simulations ◽  
Binding Pocket ◽  
Closed Channel ◽  
Agonist Action ◽  
Receptor Family

SummaryThe glycine receptor is a pentameric, neurotransmitter-activated ion channel that transitions between closed/resting, open and desensitized states. Glycine, a full agonist, produces an open channel probability (Po) of ∼1.0 while partial agonists, such as taurine and γ-amino butyric acid (GABA) yield submaximal Po values. Despite extensive studies of pentameric Cys-loop receptors, there is little knowledge of the molecular mechanisms underpinning partial agonist action and how the receptor transitions from the closed to open and to desensitized conformations. Here we use electrophysiology and molecular dynamics (MD) simulations, together with a large ensemble of single particle cryo-EM reconstructions, to show how agonists populate agonist-bound yet closed channel states, thus explaining their lesser efficacy, yet also populate agonist-bound open and desensitized states. Measurements within the neurotransmitter binding pocket, as a function of bound agonist, provide a metric to correlate the extent of agonist-induced conformational changes to open channel probability across the Cys-loop receptor family.

Apigenin acts as a partial agonist action at estrogen receptors in vivo

2021 ◽  
pp. 174175
Author(s):  
Lu Yao ◽  
Zhuoyan Fan ◽  
Shiwen Han ◽  
Na Sun ◽  
Huilian Che
Keyword(s):  
Estrogen Receptors ◽  
Partial Agonist ◽  
Agonist Action

scholarly journals The structural basis for agonist and partial agonist action on a β1-adrenergic receptor

Nature ◽  
2011 ◽  
Vol 469 (7329) ◽  
pp. 241-244 ◽  
Author(s):  
Tony Warne ◽  
Rouslan Moukhametzianov ◽  
Jillian G. Baker ◽  
Rony Nehmé ◽  
Patricia C. Edwards ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Partial Agonist ◽  
Structural Basis ◽  
Agonist Action

Mechanism of synaptic inhibition by noradrenaline acting at α 2 -adrenoceptors

1988 ◽  
Vol 234 (1274) ◽  
pp. 85-114 ◽  
Keyword(s):  
Time Course ◽  
Partial Agonist ◽  
Single Cells ◽  
Inward Rectification ◽  
Synaptic Potential ◽  
High Concentration ◽  
Agonist Action ◽  
Neuronal Inhibition ◽  
Adrenoceptor Agonists ◽  
Pipette Tip

The actions of agonists at α 2 -adrenoceptors were investigated on single cells of the submucous plexus of the guinea pig small intestine. Intracellular recordings were made from neurons in vitro , and noradrenaline and other agonists were applied by adding them to the superfusion solution. The actions of noradrenaline released from terminals of sympathetic nerves was also studied by stimulating the nerves and recording the inhibitory postsynaptic current; this current can be mimicked by brief applications of noradrenaline from a pipette tip positioned within 50 μm of the neuron. The α 2 -adrenoceptor-bound noradrenaline with an apparent dissociation constant of 15 μM, determined by the method of partial irreversible receptor inactivation: clonidine and 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14304) had dissociation con­stants of 36 nM and 2.5 μM respectively. Noradrenaline and UK 14304 caused maximal hyperpolarizations, or outward currents; clonidine was a full agonist in only 4 of 35 cells, a partial agonist in 25 cells, and without effect in 4 cells. Clonidine acted as a competitive antagonist of noradrenaline in those cells in which it lacked agonist action; its dissociation equilibrium constant determined by Schild analysis was about 20 nM. The potassium conductance increased by the α 2 -adrenoceptor agonists, whether they were applied exogenously or released by stimulation of presynaptic nerves, showed marked inward rectification. The neurons showed inward rectification also in the absence of agonist; both types of rectification were eliminated by rubidium (2 mM), barium (3–30 μM) and caesium (2 mM). When the recording electrodes contained the non-hydrolysable derivative of guanosine 5′-triphosphate (GTP), guanosine 5′- O -(3-thiotriphosphate, GTP-γ-S), the effects of applied α 2 -adrenoceptor agonists did not reverse when they were washed from the tissue, imply­ing that GTP hydrolysis is necessary for the termination of agonist action. Pretreatment with pertussis toxin abolished the inhibitory synaptic potential (IPSP) and agonist-induced hyperpolarizations. Phorbol 12, 13-dibutyrate, forskolin, cholera toxin and sodium fluoride did not affect the responses to α 2 -adrenoceptor agonists. The synaptic hyperpolarization resulting from sympathetic nerve stimulation, or the hyperpolarization evoked by a brief (3–5 ms) application of noradrenaline, began after a latency of about 30 and 60 ms respectively. The decline of the synaptic current was exponential with time constant about 300 ms: when a high concentration of the antagonist idazoxan was applied suddenly (by applying pressure to a pipette tip positioned near the neuron), a steady-state hyperpolarization evoked by superfusion with noradrenaline was terminated with a similar time-course. This result suggests the decline of the synaptic response may be determined by the dissociation rate of noradrenaline; it is also possible that an intermediate biochemical process may underlie the decay of the synaptic potential. Many of the features of the response to noradrenaline are noted to be the same as for inhibitory synaptic potentials caused by acetylcholine acting on the cardiac type of M 2 muscarinic receptor. It is proposed that synaptically released noradrenaline binds to the α 2 receptor and brings about neuronal inhibition by activating a GTP binding protein within the membrane, which in turn leads to an increased opening of inwardly rectifying potassium channels.

scholarly journals Kinetic Determinants of Agonist Action at the Recombinant Human Glycine Receptor

2003 ◽  
Vol 549 (2) ◽  
pp. 361-374 ◽  
Author(s):  
Trevor M. Lewis ◽  
Peter R. Schofield ◽  
Annette M. L. McClellan
Keyword(s):  
Glycine Receptor ◽  
Agonist Action

Structural basis for partial agonist action at ionotropic glutamate receptors

2003 ◽  
Vol 6 (8) ◽  
pp. 803-810 ◽  
Author(s):  
Rongsheng Jin ◽  
Tue G Banke ◽  
Mark L Mayer ◽  
Stephen F Traynelis ◽  
Eric Gouaux
Keyword(s):  
Glutamate Receptors ◽  
Partial Agonist ◽  
Ionotropic Glutamate Receptors ◽  
Structural Basis ◽  
Agonist Action

scholarly journals Comparison of Taurine- and Glycine-induced Conformational Changes in the M2-M3 Domain of the Glycine Receptor

2004 ◽  
Vol 279 (19) ◽  
pp. 19559-19565 ◽  
Author(s):  
Nian-Lin R. Han ◽  
John D. Clements ◽  
Joseph W. Lynch
Keyword(s):  
Conformational Changes ◽  
Reaction Rate ◽  
Partial Agonist ◽  
Glycine Receptor ◽  
Reaction Rates ◽  
Structural Basis ◽  
Surface Accessibility ◽  
Partial Agonists ◽  
Substituted Cysteine Accessibility ◽  
Receptor Family

In the ionotropic glutamate receptor, the global conformational changes induced by partial agonists are smaller than those induced by full agonists. However, in the pentameric ligand-gated ion channel receptor family, the structural basis of partial agonism is not understood. This study investigated whether full and partial agonists induce different conformation changes in the glycine receptor chloride channel (GlyR). A substituted cysteine accessibility analysis demonstrated previously that glycine binding induced an increase in surface accessibility of all residues from Arg271to Lys276in the M2-M3 domain of the homomeric α1 GlyR. Here we compare the surface accessibility changes induced by the full agonist, glycine, and the partial agonist, taurine. In GlyRs incorporating the A272C, S273C, L274C, or P275C mutation, the reaction rate of the cysteine-specific compound, methanethiosulfonate ethyltrimethylammonium, depended on how strongly the receptors were activated but was agonist-independent. Reaction rates could not be compared in the R271C and K276C mutant GlyRs because methanethiosulfonate ethyltrimethylammonium did not modify the extremely small currents induced by saturating taurine or equivalent low glycine concentrations. The results indicate that bound taurine and glycine molecules impose identical conformational changes to the M2-M3 domain. We therefore conclude that the higher efficacy of glycine is due to an increased ability to stabilize a common activated configuration.

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