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The additional ACh binding site at the α4(+)/α4(-) interface of the (α4β2)2α4 nicotinic ACh receptor contributes to desensitization.
Benallegue N
,
Mazzaferro S
,
Alcaino C
,
Bermudez I
.
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Nicotinic ACh (α4β2)2α4 receptors are highly prone to desensitization by prolonged exposure to low concentrations of agonist. Here, we report on the sensitivity of the three agonist sites of the (α4β2)2α4 to desensitization induced by prolonged exposure to ACh. We present electrophysiological data that show that the agonist sites of the (α4β2)2α4 receptor have different sensitivity to desensitization and that full receptor occupation decreases sensitivity to desensitization. Two-electrode voltage-clamp electrophysiology was used to study the desensitization of concatenated (α4β2)2α4 receptors expressed heterologously in Xenopus oocytes. Desensitization was assessed by measuring the degree of functional inhibition caused by prolonged exposure to ACh, as measured under equilibrium conditions. We used the single-point mutation α4W182A to measure the contribution of individual agonist sites to desensitization. (α4β2)2α4 receptors are less sensitive to activation and desensitization by ACh than (α4β2)2β2 receptors. Incorporation of α4W182A into any of the agonist sites of concatenated (α4β2)2α4 receptors decreased sensitivity to activation and desensitization but the effects were more pronounced when the mutation was introduced into the α4(+)/α4(-) interface. The findings suggest that the agonist sites in (α4β2)2α4 receptors are not functionally equivalent. The agonist site at the α4(+)/α4(-) interface defines the sensitivity of (α4β2)2α4 receptors to agonist-induced activation and desensitization. Functional differences between (α4β2)2α4 and (α4β2)2β2 receptors might shape the physiological and behavioural responses to nicotinic ligands when the receptors are exposed to nicotinic ligands for prolonged periods of times.
Akk,
Activation of muscle nicotinic acetylcholine receptor channels by nicotinic and muscarinic agonists.
1999, Pubmed
Akk,
Activation of muscle nicotinic acetylcholine receptor channels by nicotinic and muscarinic agonists.
1999,
Pubmed
Akk,
Aromatics at the murine nicotinic receptor agonist binding site: mutational analysis of the alphaY93 and alphaW149 residues.
2001,
Pubmed
Alexander,
Guide to Receptors and Channels (GRAC), 5th edition.
2011,
Pubmed
Auerbach,
The gating isomerization of neuromuscular acetylcholine receptors.
2010,
Pubmed
Baumann,
Individual properties of the two functional agonist sites in GABA(A) receptors.
2003,
Pubmed
,
Xenbase
Bertrand,
Unconventional pharmacology of a neuronal nicotinic receptor mutated in the channel domain.
1992,
Pubmed
,
Xenbase
Bertrand,
Properties of neuronal nicotinic acetylcholine receptor mutants from humans suffering from autosomal dominant nocturnal frontal lobe epilepsy.
1998,
Pubmed
,
Xenbase
Buisson,
The unusual nature of epibatidine responses at the alpha4beta2 nicotinic acetylcholine receptor.
2000,
Pubmed
Carbone,
Pentameric concatenated (alpha4)(2)(beta2)(3) and (alpha4)(3)(beta2)(2) nicotinic acetylcholine receptors: subunit arrangement determines functional expression.
2009,
Pubmed
,
Xenbase
Chavez-Noriega,
Pharmacological characterization of recombinant human neuronal nicotinic acetylcholine receptors h alpha 2 beta 2, h alpha 2 beta 4, h alpha 3 beta 2, h alpha 3 beta 4, h alpha 4 beta 2, h alpha 4 beta 4 and h alpha 7 expressed in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
Corringer,
Critical elements determining diversity in agonist binding and desensitization of neuronal nicotinic acetylcholine receptors.
1998,
Pubmed
,
Xenbase
Fenster,
Influence of subunit composition on desensitization of neuronal acetylcholine receptors at low concentrations of nicotine.
1997,
Pubmed
,
Xenbase
Giniatullin,
Desensitization of nicotinic ACh receptors: shaping cholinergic signaling.
2005,
Pubmed
Gopalakrishnan,
Stable expression, pharmacologic properties and regulation of the human neuronal nicotinic acetylcholine alpha 4 beta 2 receptor.
1996,
Pubmed
Gotti,
Partial deletion of the nicotinic cholinergic receptor alpha 4 or beta 2 subunit genes changes the acetylcholine sensitivity of receptor-mediated 86Rb+ efflux in cortex and thalamus and alters relative expression of alpha 4 and beta 2 subunits.
2008,
Pubmed
Grady,
Low concentrations of nicotine differentially desensitize nicotinic acetylcholine receptors that include α5 or α6 subunits and that mediate synaptosomal neurotransmitter release.
2012,
Pubmed
Harpsøe,
Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors.
2011,
Pubmed
Jha,
Acetylcholine receptor channels activated by a single agonist molecule.
2010,
Pubmed
Kuryatov,
Acetylcholine receptor extracellular domain determines sensitivity to nicotine-induced inactivation.
2000,
Pubmed
,
Xenbase
Lester,
Activation and desensitization of heteromeric neuronal nicotinic receptors: implications for non-synaptic transmission.
2004,
Pubmed
Mantione,
Allosteric modulators of α4β2 nicotinic acetylcholine receptors: a new direction for antidepressant drug discovery.
2012,
Pubmed
Marks,
Two pharmacologically distinct components of nicotinic receptor-mediated rubidium efflux in mouse brain require the beta2 subunit.
1999,
Pubmed
Marks,
86Rb+ efflux mediated by alpha4beta2*-nicotinic acetylcholine receptors with high and low-sensitivity to stimulation by acetylcholine display similar agonist-induced desensitization.
2010,
Pubmed
Matsushima,
Mutation (Ser284Leu) of neuronal nicotinic acetylcholine receptor alpha 4 subunit associated with frontal lobe epilepsy causes faster desensitization of the rat receptor expressed in oocytes.
2002,
Pubmed
,
Xenbase
Mazzaferro,
Additional acetylcholine (ACh) binding site at alpha4/alpha4 interface of (alpha4beta2)2alpha4 nicotinic receptor influences agonist sensitivity.
2011,
Pubmed
,
Xenbase
Moroni,
alpha4beta2 nicotinic receptors with high and low acetylcholine sensitivity: pharmacology, stoichiometry, and sensitivity to long-term exposure to nicotine.
2006,
Pubmed
,
Xenbase
Moroni,
Non-agonist-binding subunit interfaces confer distinct functional signatures to the alternate stoichiometries of the alpha4beta2 nicotinic receptor: an alpha4-alpha4 interface is required for Zn2+ potentiation.
2008,
Pubmed
,
Xenbase
Nelson,
Alternate stoichiometries of alpha4beta2 nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase
Paradiso,
Nicotine is highly effective at producing desensitization of rat alpha4beta2 neuronal nicotinic receptors.
2003,
Pubmed
Rayes,
Number and locations of agonist binding sites required to activate homomeric Cys-loop receptors.
2009,
Pubmed
Rode,
Positive allosteric modulation of α4β2 nAChR agonist induced behaviour.
2012,
Pubmed
Steinbach,
Mechanism of action of the nicotinic acetylcholine receptor.
1990,
Pubmed
Taly,
Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system.
2009,
Pubmed
Tapia,
Ca2+ permeability of the (alpha4)3(beta2)2 stoichiometry greatly exceeds that of (alpha4)2(beta2)3 human acetylcholine receptors.
2007,
Pubmed
,
Xenbase
Timmermann,
Augmentation of cognitive function by NS9283, a stoichiometry-dependent positive allosteric modulator of α2- and α4-containing nicotinic acetylcholine receptors.
2012,
Pubmed
,
Xenbase
Xiu,
Nicotine binding to brain receptors requires a strong cation-pi interaction.
2009,
Pubmed
,
Xenbase
Zhang,
Desensitization of alpha7 nicotinic receptor is governed by coupling strength relative to gate tightness.
2011,
Pubmed
,
Xenbase
daCosta,
Stoichiometry for drug potentiation of a pentameric ion channel.
2013,
Pubmed
