5-Hydroxyindole potentiates human α7 nicotinic receptor-mediated responses and enhances acetylcholine-induced glutamate release in cerebellar slices

Zwart, Ruud; Filippi, Giovanna De; Broad, Lisa M.; McPhie, Gordon; Pearson, Kathy H.; Baldwinson, Tristan; Sher, Emanuele

doi:10.1016/s0028-3908(02)00094-1

Cited by 100 publications

(97 citation statements)

References 42 publications

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“…The fact that potentiation occurred within seconds and was reversible suggests that incorporation of receptors, whether newly synthesized or drawn from intracellular stores, seems an unlikely explanation. As has been proposed for the potentiating effect of certain compounds on other nAChRs (Conroy et al 2003;Curtis et al 2002;Hurst et al 2005;Krause et al 1998;Zwart et al 2002), the most likely interpretation of the present results is that ryanodine acts as a positive allosteric effector, recognizing a specific binding site within the receptor protein. Another formal possibility is that ryanodine is having its effect through Fconformational coupling_ between hair cell AChRs and ryanodine receptors (RyR) as occurs during calcium release from sarcoplasmic reticulum in skeletal muscle.…”

Section: Figsupporting

confidence: 80%

Ryanodine is a Positive Modulator of Acetylcholine Receptor Gating in Cochlear Hair Cells

Martín

Ballestero

Katz

et al. 2007

JARO

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The efferent synaptic specialization of hair cells includes a near-membrane synaptic cistern, whose presence suggests a role for internal calcium stores in cholinergic inhibition. Calcium release channels from internal stores include Fryanodine receptors_, whose participation is usually demonstrated by sensitivity to the eponymous plant alkaloid, ryanodine. However, use of this and other store-active compounds on hair cells could be confounded by the unusual pharmacology of the a9a10-containing hair cell nicotinic cholinergic receptor (nAChR), which has been shown to be antagonized by a broad spectrum of compounds. Surprisingly, we found that ryanodine, rather than antagonizing, is a positive modulator of the a9a10 nAChR expressed in Xenopus oocytes, the first such compound to be found. The effect of ryanodine was to increase the apparent affinity and efficacy for acetylcholine (ACh). Correspondingly, ACh-evoked currents through the isolated cholinergic receptors of inner hair cells in excised mouse cochleas were approximately doubled by 200 mM ryanodine, a concentration that inhibits gating of the ryanodine receptor itself. This unusual positive modulation was not unique to the mammalian receptor. The response to ACh of chicken Fshort_ hair cells likewise was enhanced in the presence of 100 mM ryanodine. This facilitatory effect on current through the AChR could enhance brief (õ1 s) activation of associated calciumdependent K + (SK) channels in both chicken short hair cells and rat outer hair cells. This novel effect of ryanodine provides new opportunities for the design of compounds that potentiate a9a10-mediated responses and for potential inner ear therapeutics based on this interaction.

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Section: Figsupporting

confidence: 80%

Ryanodine is a Positive Modulator of Acetylcholine Receptor Gating in Cochlear Hair Cells

Martín

Ballestero

Katz

et al. 2007

JARO

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“…Treatment with 1 M PNU-120596 virtually eliminated the decay of current during the 1 s challenge with ACh. This property of PNU-120596 is in contrast to that of other PAMs described previously for the ␣7 nAChR, which appear to have relatively little or no effect on the decay of the macroscopic currents (Krause et al, 1998;Zwart et al, 2002;Chimienti et al, 2003;Conroy et al, 2003;Zbarsky et al, 2004). As illustrated in Figure 3B, the effects of PNU-120596 were maintained during a prolonged exposure.…”

Section: Pnu-120596 Selectively Enhances the Function Of ␣ 7 Nachrsmentioning

confidence: 57%

“…A different approach would be to administer a nicotinic positive allosteric modulator (PAM) that can reinforce the endogenous cholinergic neurotransmission without directly stimulating the target receptors (for review, see Maelicke, 2000;Albuquerque et al, 2001). Several PAMs have been identified that increase the potency and/or maximal efficacy of agonists for the ␣7 nAChR; however, none of these agents has been shown to modify neuronal or circuit level activity in vivo (Krause et al, 1998;Zwart et al, 2002;Chimienti et al, 2003;Conroy et al, 2003;Zbarsky et al, 2004). Here, we report the discovery of a novel PAM of the ␣7 nAChR, 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596), which not only increases the potency and maximal efficacy of agonists but also dramatically prolongs the duration of the agonist-evoked macroscopic currents.…”

Section: Introductionmentioning

confidence: 99%

A Novel Positive Allosteric Modulator of the α7 Neuronal Nicotinic Acetylcholine Receptor:In VitroandIn VivoCharacterization

Hurst¹,

Hajós²,

Raggenbass³

et al. 2005

J. Neurosci.

419

473

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Several lines of evidence suggest a link between the ␣7 neuronal nicotinic acetylcholine receptor (nAChR) and brain disorders including schizophrenia, Alzheimer's disease, and traumatic brain injury. The present work describes a novel molecule, 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596), which acts as a powerful positive allosteric modulator of the ␣7 nAChR. Discovered in a high-throughput screen, PNU-120596 increased agonist-evoked calcium flux mediated by an engineered variant of the human ␣7 nAChR. Electrophysiology studies confirmed that PNU-120596 increased peak agonist-evoked currents mediated by wild-type receptors and also demonstrated a pronounced prolongation of the evoked response in the continued presence of agonist. In contrast, PNU-120596 produced no detectable change in currents mediated by ␣4␤2, ␣3␤4, and ␣9␣10 nAChRs. PNU-120596 increased the channel mean open time of ␣7 nAChRs but had no effect on ion selectivity and relatively little, if any, effect on unitary conductance. When applied to acute hippocampal slices, PNU-120596 increased the frequency of ACh-evoked GABAergic postsynaptic currents measured in pyramidal neurons; this effect was suppressed by TTX, suggesting that PNU-120596 modulated the function of ␣7 nAChRs located on the somatodendritic membrane of hippocampal interneurons. Accordingly, PNU-120596 greatly enhanced the ACh-evoked inward currents in these interneurons. Systemic administration of PNU-120596 to rats improved the auditory gating deficit caused by amphetamine, a model proposed to reflect a circuit level disturbance associated with schizophrenia. Together, these results suggest that PNU-120596 represents a new class of molecule that enhances ␣7 nAChR function and thus has the potential to treat psychiatric and neurological disorders.

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“…Both 5-HT and 5-HI are metabolites of tryptophan (Mannaioni et al, 2003). 5-HI has been shown to increase release of neurotransmitter in the cerebellum and hippocampus (Zwart et al, 2002;Mannaioni et al, 2003) and triggers convulsion in rats (Mannaioni et al, 2003). 5-HI is a positive modulator of the 5-HT 3 receptor (Kooyman et al, 1993;van Hooft et al, 1997;Gunthorpe & Lummis, 1999) and α7 nicotinic acetylcholine receptor (Zwart et al, 2002;Selina Mok & Kew, 2006).…”

Section: Introductionmentioning

confidence: 99%

The L293 residue in transmembrane domain 2 of the 5-HT3A receptor is a molecular determinant of allosteric modulation by 5-hydroxyindole

Lovinger

2008

Neuropharmacology

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Allosteric modulation of ligand-gated ion channels can play important roles in shaping synaptic transmission. The function of the 5-hydroxytryptamine (serotonin) type 3 (5-HT 3 ) receptor, a member of the Cys-loop ligand-gated ion channel superfamily, is modulated by a variety of compounds such as alcohols, anesthetics and 5-hydroxyindole (5-HI). In the present study, the molecular determinants of allosteric modulation by 5-HI were explored in N1E-115 neuroblastoma cells expressing the native 5-HT 3 receptor and HEK 293 cells transfected with the recombinant 5-HT 3A receptor using molecular biology and whole-cell patch-clamp techniques. 5-HI potentiated 5-HT-activated currents in both N1E-115 cells and HEK 293 cells, and significantly decreased current desensitization and deactivation. Substitution of Leu293 (L293, L15′) in the second transmembrane domain (TM2) with cysteine (L293C) or serine (L293S) abolished 5-HI modulation. Other mutations in the TM2 domain, such as D298A and T284F, failed to alter 5-HI modulation. The L293S mutation enhanced dopamine efficacy and converted 5-HI into a partial agonist at the mutant receptor. These data suggest that 5-HI stabilizes the 5-HT 3A receptor in the open state by decreasing both desensitization and 5-HT unbinding/channel closing; and L293 is a common site for both channel gating and allosteric modulation by 5-HI. Our observations also indicate existence of a second 5-HI recognition site on the 5-HT 3A receptor which may overlap with the 5-HT binding site and is not involved in the positive modulation by 5-HI. These findings support the idea that there are two discrete sites for 5-HI allosteric modulation and direct activation in the 5-HT 3A receptor.

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5-Hydroxyindole potentiates human α7 nicotinic receptor-mediated responses and enhances acetylcholine-induced glutamate release in cerebellar slices

Cited by 100 publications

References 42 publications

Ryanodine is a Positive Modulator of Acetylcholine Receptor Gating in Cochlear Hair Cells

Ryanodine is a Positive Modulator of Acetylcholine Receptor Gating in Cochlear Hair Cells

A Novel Positive Allosteric Modulator of the α7 Neuronal Nicotinic Acetylcholine Receptor:In VitroandIn VivoCharacterization

The L293 residue in transmembrane domain 2 of the 5-HT3A receptor is a molecular determinant of allosteric modulation by 5-hydroxyindole

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