Weber KH

References (3)

Title : Agonist responses of neuronal nicotinic acetylcholine receptors are potentiated by a novel class of allosterically acting ligands - Schrattenholz_1996_Mol.Pharmacol_49_1
Author(s) : Schrattenholz A , Pereira EF , Roth U , Weber KH , Albuquerque EX , Maelicke A
Ref : Molecular Pharmacology , 49 :1 , 1996
Abstract : Similar to the gamma-aminobutyric acidA receptor and the N-methyl-D-aspartate subtype of glutamate receptor, neuronal nicotinic acetylcholine receptors are subject to positive modulatory control by allosterically acting ligands. Exogenous ligands such as galanthamine and the neurotransmitter 5-hydroxytryptamine, when applied in submicromolar concentrations with nicotinic agonists, significantly increase the frequency of opening of nicotinic receptor channels and potentiate agonist-activated currents. Because these effects have been shown to be blocked by the monoclonal antibody FK1, they are mediated by binding sites that are located on alpha subunits of nicotinic receptors and distinct from those for acetylcholine and acetylcholine-competitive ligands. At higher concentrations, the potentiating effect of these ligands decreases and is eventually overcome by an inhibition of the agonist-induced response. The sensitizing actions of galanthamine, 5-hydroxytryptamine, and related compounds, at submicromolar concentrations, may reflect the existence of cross-talk between adjacent neuroreceptors and synapses in the central nervous system and thus suggests the formation of transiently active chemical networks in the vertebrate brain.
ESTHER : Schrattenholz_1996_Mol.Pharmacol_49_1
PubMedSearch : Schrattenholz_1996_Mol.Pharmacol_49_1
PubMedID: 8569694

Title : Noncompetitive agonism at nicotinic acetylcholine receptors\; functional significance for CNS signal transduction - Maelicke_1995_J.Recept.Signal.Transduct.Res_15_333
Author(s) : Maelicke A , Schrattenholz A , Storch A , Schroder B , Gutbrod O , Methfessel C , Weber KH , Pereira EE , Alkondon M , Albuquerque EX
Ref : J Recept Signal Transduct Res , 15 :333 , 1995
Abstract : The alkaloids (-)physostigmine (Phy), galanthamine (Gal) and codeine (Cod), and several derivatives and homologous compounds, can act as noncompetitive agonists (NCA) of nicotinic acetylcholine receptors (nAChR) from Torpedo electrocytes, frog and mammalian muscle cells, clonal rat pheochromocytoma cells, cultured hippocampal neurons and several ectopic expression systems, by interacting with a binding site on the alpha-subunits of these nAChRs that is insensitive to the natural transmitter, acetylcholine (ACh), and ACh-competitive agonists and antagonists. Several endogenous ligands, including opioid-type compounds, can also act via this site, albeit at higher concentrations than is typical for the interaction with their cognate receptors. The NCA-evoked responses can be observed at the single-channel level but they do not summate to significant macroscopic currents, suggesting that the major role of NCAs is to act as "co-agonists", thereby potentiating nAChR channel activation by the natural transmitter. In more general terms, noncompetitive agonists may constitute part of a "chemical network", by which intercellular messengers, in addition to serving their cognate receptors, could modulate the sensitivity of other neuroreceptors to their archetypic ligands. Such a mode of action would make centrally acting NCAs interesting candidate drugs in the treatment of neuro-degenerative diseases.
ESTHER : Maelicke_1995_J.Recept.Signal.Transduct.Res_15_333
PubMedSearch : Maelicke_1995_J.Recept.Signal.Transduct.Res_15_333
PubMedID: 8903949

Title : Physostigmine, galanthamine and codeine act as 'noncompetitive nicotinic receptor agonists' on clonal rat pheochromocytoma cells - Storch_1995_Eur.J.Pharmacol_290_207
Author(s) : Storch A , Schrattenholz A , Cooper JC , Abdel Ghani EM , Gutbrod O , Weber KH , Reinhardt S , Lobron C , Hermsen B , Soskic V , Pereira EF , Albuquerque EX , Methfessel C , Maelicke A
Ref : European Journal of Pharmacology , 290 :207 , 1995
Abstract : The acetylcholine esterase inhibitor (-)-physostigmine has been shown to act as agonist on nicotinic acetylcholine receptors from muscle and brain, by binding to sites on the alpha-polypeptide that are distinct from those for the natural transmitter acetylcholine (Schrder et al., 1994). In the present report we show that (-)-physostigmine, galanthamine, and the morphine derivative codeine activate single-channel currents in outside-out patches excised from clonal rat pheochromocytoma (PC12) cells. Although several lines of evidence demonstrate that the three alkaloids act on the same channels as acetylcholine, the competitive nicotinic antagonist methyllycaconitine only inhibited channel activation by acetylcholine but not by (-)-physostigmine, galanthamine or codeine. In contrast, the monoclonal antibody FK1, which competitively inhibits (-)-physostigmine binding to nicotinic acetylcholine receptors, did not affect channel activation by acetylcholine but inhibited activation by (-)-physostigmine, galanthamine and codeine. The three alkaloids therefore act via binding sites distinct from those for acetylcholine, in a 'noncompetitive' fashion. The potency of (-)-physostigmine and related compounds to act as a noncompetitive agonist is unrelated to the level of acetylcholine esterase inhibition induced by these drugs. (-)-Physostigmine, galanthamine and codeine do not evoke sizable whole-cell currents, which is due to the combined effects of low open-channel probability, slow onset and slow inactivation of response. In contrast, they sensitize PC12 cell nicotinic receptors in their submaximal response to acetylcholine. While the abundance of nicotinic acetylcholine receptor isoforms expressed in PC12 cells excludes identification of specific nicotinic acetylcholine receptor subtypes that interact with noncompetitive agonists, the identical patterns of single-channel current amplitudes observed with acetylcholine and with noncompetitive agonists suggested that all PC12 cell nicotinic acetylcholine receptor subtypes that respond to acetylcholine also respond to noncompetitive agonist. The action of noncompetitive agonists therefore seems to be highly conserved between nicotinic acetylcholine receptor subtypes, in agreement with the high level of structural conservation in the sequence region harboring major elements of this site.
ESTHER : Storch_1995_Eur.J.Pharmacol_290_207
PubMedSearch : Storch_1995_Eur.J.Pharmacol_290_207
PubMedID: 7589215