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

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

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

Partial agonism by gastrin for a cholecystokinin receptor mediating pepsinogen secretion

1993 ◽  
Vol 265 (5) ◽  
pp. G865-G872
Author(s):  
L. H. Tang ◽  
M. D. Miller ◽  
J. R. Goldenring ◽  
I. M. Modlin ◽  
S. J. Hersey
Keyword(s):  
Partial Agonist ◽  
Specific Binding ◽  
Receptor Occupancy ◽  
Structural Basis ◽  
Tyrosine Residue ◽  
Gastric Glands ◽  
Cholecystokinin Receptor ◽  
Isolated Gastric Glands ◽  
Pepsinogen Secretion ◽  
Type Receptor

Isolated gastric glands from rabbit were used to characterize the functional cholecystokinin (CCK)-like peptide receptors that mediate pepsinogen secretion. Pepsinogen secretion was stimulated by both CCK octapeptide sulfate (CCK-8) and A-71378, a selective CCK-A-type receptor agonist, with similar mean effective doses (1.0 and 0.8 nM, respectively). Compared with CCK-8, gastrin-17 (G-17-I) showed reduced potency and only partial efficacy for stimulation of pepsinogen secretion while inhibiting the maximal CCK-8-stimulated response. The nonpeptide inhibitors, asperlicin and L-364,718, inhibited pepsinogen secretion with identical pA2 values for antagonism of both CCK and gastrin, indicating that both peptides interact with the same functional receptor. Specific binding of [3H]CCK-8 to isolated chief cell membranes was displaced fully by both CCK and gastrin, indicating full receptor occupancy by both peptides. A novel synthetic peptide analogue, pseudogastrin [(Glu)5-Ala-Tyr-Nle-Gly-Trp-Nle-Asp-Phe-NH2], was used to investigate the structural basis for the lower potency and efficacy of G-17-I. The potency of CCK and gastrin analogues for pepsinogen secretion was found to be dependent on both sulfation of a tyrosine residue and the position of the tyrosine residue relative to the COOH-terminal phenylalanine amide. The efficacy appears to be determined partially by the extended NH2-terminal sequence of G-17-I. The results of the present study are interpreted to show that pepsinogen secretion is mediated by a CCK-A-type receptor and gastrin acts at the same receptor as a partial agonist.

Secretory response of dispersed rat submandibular cells. II. Mucin secretion

1980 ◽  
Vol 238 (3) ◽  
pp. C99-C106 ◽  
Author(s):  
D. O. Quissell ◽  
K. A. Barzen
Keyword(s):  
Adrenergic Receptor ◽  
Partial Agonist ◽  
Receptor Activation ◽  
Secretory Response ◽  
Mucin Secretion ◽  
Beta Adrenergic Receptor ◽  
Beta Adrenergic ◽  
Alpha Adrenergic Receptor ◽  
Median Effective Concentration ◽  
Higher Doses

The secretory response of dispersed rat submandibular cells as it relates to the secretion of D-[1-14C]glucosamine hydrochloride-labeled mucin following sympathomimetic and parasympathomimetic stimulation was evaluated. The adrenergic agonists (-)-norepinephrine and (-)-epinephrine were found to have equal efficacy and potency with a median effective concentration (EC50) of 7.1 x 10(-7) M. (-)-Isoproterenol was found to be acting as a "partial" agonist and had an EC50 of 3.9 x 10(-7) M. (-)-Phenylephrine addition resulted in a small, but significant, secretion of mucin at higher doses tested (10(-4) M--10(-3) M). Neither cholinergic nor alpha-adrenergic receptor stimulation was able to elicit a net increase in the secretion of mucin. However alpha-adrenergic receptor activation in conjunction with beta-adrenergic receptor activation facilitated the rate of secretion. Extracellular Ca2+ and Mg2+ were not required for the secretion of mucin, but extracellular Ca2+ enhanced the rate of secretion following alpha- and beta-adrenergic receptor activation. However extracellular Ca2+ did not enhance mucin secretion following beta-adrenergic receptor activation. Both cellular Ca2+ and beta-adrenergic receptor activation were required to elicit a secretory response following sympathomimetic stimulation.

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.

Structural basis of the transactivation deficiency of the human PPARγ F360L mutant associated with familial partial lipodystrophy

2014 ◽  
Vol 70 (7) ◽  
pp. 1965-1976 ◽  
Author(s):  
Clorinda Lori ◽  
Alessandra Pasquo ◽  
Roberta Montanari ◽  
Davide Capelli ◽  
Valerio Consalvi ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Conformational Changes ◽  
Partial Agonist ◽  
Salt Bridge ◽  
Van Der Waals Interactions ◽  
Structural Basis ◽  
Wild Type ◽  
Partial Lipodystrophy ◽  
X Ray ◽  
Familial Partial Lipodystrophy

The peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate glucose and lipid metabolism. The role of PPARs in several chronic diseases such as type 2 diabetes, obesity and atherosclerosis is well known and, for this reason, they are the targets of antidiabetic and hypolipidaemic drugs. In the last decade, some rare mutations in human PPARγ that might be associated with partial lipodystrophy, dyslipidaemia, insulin resistance and colon cancer have emerged. In particular, the F360L mutant of PPARγ (PPARγ2 residue 388), which is associated with familial partial lipodystrophy, significantly decreases basal transcriptional activity and impairs stimulation by synthetic ligands. To date, the structural reason for this defective behaviour is unclear. Therefore, the crystal structure of PPARγ F360L together with the partial agonist LT175 has been solved and the mutant has been characterized by circular-dichroism spectroscopy (CD) in order to compare its thermal stability with that of the wild-type receptor. The X-ray analysis showed that the mutation induces dramatic conformational changes in the C-terminal part of the receptor ligand-binding domain (LBD) owing to the loss of van der Waals interactions made by the Phe360 residue in the wild type and an important salt bridge made by Arg357, with consequent rearrangement of loop 11/12 and the activation function helix 12 (H12). The increased mobility of H12 makes the binding of co-activators in the hydrophobic cleft less efficient, thereby markedly lowering the transactivation activity. The spectroscopic analysis in solution and molecular-dynamics (MD) simulations provided results which were in agreement and consistent with the mutant conformational changes observed by X-ray analysis. Moreover, to evaluate the importance of the salt bridge made by Arg357, the crystal structure of the PPARγ R357A mutant in complex with the agonist rosiglitazone has been solved.

Effect of dehydroleucodine on intestinal transit: structural basis of the interaction with the α2-adrenergic receptor

2011 ◽  
Vol 40 (8) ◽  
pp. 981-986 ◽  
Author(s):  
Graciela Haydée Wendel ◽  
Alejandra Olivia María ◽  
Carlos Fernando Aguilar ◽  
Lilian Eugenia Pelzer
Keyword(s):  
Adrenergic Receptor ◽  
Intestinal Transit ◽  
Structural Basis
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