Subunit-Dependent Modulation of Neuronal Nicotinic Receptors by Zinc

Hsiao, Bernard; Dweck, David; Luetje, Charles W.

doi:10.1523/jneurosci.21-06-01848.2001

Cited by 72 publications

(77 citation statements)

References 38 publications

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“…Divalent cations have also been shown to modulate LGIC current by interacting with binding sites on the extracellular side of the receptor, such as the N-terminal domain or M2-M3 loop. Specifically, Zn 2ϩ has been shown to transiently modify LGIC current in a voltage-independent manner (47)(48)(49). Therefore, one possibility is that Cd 2ϩ interacts with sites on the extracellular side of the receptor, where it inhibits current flow either by modulating gating (drawing the receptor into a desensitized state) or by affecting 5-HT binding at the ligand binding domain.…”

Section: Discussionmentioning

confidence: 99%

Minimal Structural Rearrangement of the Cytoplasmic Pore during Activation of the 5-HT3A Receptor

Panicker

Cruz

Arrabit

et al. 2004

Journal of Biological Chemistry

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Ligand-gated ion channel receptors mediate the response of fast neurotransmitters by opening in less than a millisecond. Here, we investigated the activation mechanism of a serotonin-gated receptor (5-HT 3A ) by systematically introducing cysteine substitutions throughout the pore-lining M1-M2 loop and M2 transmembrane domain. We hypothesized that multiple cysteines in the narrowest region of the pore, which together can form a high affinity binding site for metal cations, would reveal changes in pore structure during gating. Using cadmium (Cd 2؉ ) as a probe, two cysteine substitutions in the cytoplasmic selectivity filter, S2 C and, to a lesser extent, G-2 C, showed high affinity inhibition with Cd 2؉ Ligand-gated ion channel (LGIC) 1 receptors are responsible for rapid chemical transmission between neurons in the nervous system (1). Alterations in the response of ligand-gated receptors have profound effects on neuronal activity in the brain. For example, mutations in nicotinic acetylcholine-gated receptors (nAChRs) and glycine-gated receptors have been linked to certain forms of epilepsy and startle disease, respectively (2-4).LGIC receptors that respond to acetylcholine, ␥-aminobutyric acid, glycine, or serotonin (5-HT) possess a conserved pair of extracellular cysteines in the N-terminal domain ("Cys loop" receptors) and are composed of five subunits, each containing four putative transmembrane domains (5). Of these four domains, the second transmembrane domain (M2) lines the majority of the water-filled pore (Fig. 1A).The rapid response of LGIC receptors is achieved by the energetic coupling of agonist binding in the extracellular Nterminal domain with a "gate" located 60 Å away in the receptor pore (M2 domain) (6). Several studies with LGIC receptors suggest that the gate is situated in the middle of the M2 (6 -12) (but see Ref. 13). The primary determinants of selectivity appear to be located below the gate, near the cytoplasmic membrane surface. Mutations in the cytoplasmic end of the M2 alter ion selectivity (14 -17), and several recent studies show that by mutating sites in this region, cation-conducting LGIC can be converted to anion-conducting channels and vice versa (18 -23). Because permeability of like-charged molecules in LGIC appears to be largely dependent on size, it is believed that the narrowest region of the open LGIC pore coincides with the channel selectivity filter, which is formed by a portion of the M1-M2 loop and the cytoplasmic side of the M2 helix (16,24). Consistent with this region being narrow, site-specific mutations in the filter alter conductivity in a manner that depends upon side-chain volume (8,24). Thus, the pore of the open receptor can be envisaged as a funnel, with a wide extracellular vestibule that tapers to a constriction at the cytoplasmic side of the membrane, where ion selectivity is determined (25).What is known about the extent of movement in the cytoplasmic selectivity filter? The 9-Å three-dimensional structures of open and closed Torpedo nAChRs derived fro...

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Section: Discussionmentioning

confidence: 99%

Minimal Structural Rearrangement of the Cytoplasmic Pore during Activation of the 5-HT3A Receptor

Panicker

Cruz

Arrabit

et al. 2004

Journal of Biological Chemistry

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“…It is known that zinc potentiates the ACh current, 6,7 and that fluoxetine has a clear blocking effect on the ACh currents mediated by either muscle or neuronal nAChRs. 12,16 Figure 1 illustrates an example of these effects on oocytes expressing neuronal a4b4 nAChRs.…”

Section: Effects Of Zinc and Fluoxetine On Neuronal Nachrsmentioning

confidence: 99%

“…4 Many endogenous and exogenous substances modify the function of nAChRs. For instance, they are modulated by cations, [5][6][7][8] 5-HT, 9-13 various agonists and antagonists of different types of 5-HT receptors, [9][10][11][12]14 as well as inhibitors of monoamine transporters that are used as antidepressants. 9,12,[15][16][17][18][19][20] The most common action of clinically used antidepressants on nAChRs appears to be a noncompetitive inhibitory process, 9,12,[15][16][17][18][19][20] and it is probable that this action contributes to improving depressed mood states.…”

Section: Introductionmentioning

confidence: 99%

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Combined actions of zinc and fluoxetine on nicotinic acetylcholine receptors

2004

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Zinc and nicotinic acetylcholine receptors (nAChRs) seem to be associated with major depression, and some antidepressants, including fluoxetine (Prozac), antagonize nAChRs. Therefore, a study was made of the modulation of neuronal a4b4 and muscle a1b1gd nAChRs, expressing in oocytes, by the combined action of zinc and fluoxetine. At a holding potential of -60 mV, 200 mM zinc increased by 361% the currents elicited by acetylcholine (ACh currents) for a4b4 and by 182% for a1b1gd nAChRs. In contrast, 5 mM fluoxetine reduced the ACh currents to 31% for a4b4 and to 45% for a1b1gd nAChRs. Additionally, fluoxetine reduced more the ACh currents in the presence of zinc: to 17% for a4b4 and to 19% for a1b1gd nAChRs, and after washing out the fluoxetine the ACh current did not recover its zinc-potentiated value. Moreover, when ACh-activated nAChRs were exposed first to fluoxetine and then zinc was added, the potentiating effect of zinc was very small for muscle nAChRs and was nil for neuronal receptors. Thus, the inhibiting effect of fluoxetine prevails over the potentiating action of zinc. Finally, the effects of both zinc and fluoxetine were voltage independent, indicating that these substances interact outside the ion channel. As fluoxetine nullifies the effects of zinc, it appears that both substances interact in the same site. These results should help understand better the roles played by zinc, antidepressants, nAChRs and their combination in brain functions and in the treatment of depression.

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“…In common with all members of the pLGIC family, the current responses of ␣4␤2 nAChR can be enhanced by a variety of agents, including Zn 2ϩ (9,10), the endogenous steroid 17␤-estradiol (␤EST) (11), desformylflustrabromine (dFBr) (12,13), and synthetic ligands CMPI (14), LY2087101 (15), and NS206 and NS9283 (16,17). The identification of positive allosteric modulator (PAM) binding sites in the TMD of the ␣4 subunit, e.g.…”

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confidence: 99%

Role of the Cys Loop and Transmembrane Domain in the Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors

Alcaino

Musgaard

Minguez

et al. 2017

Journal of Biological Chemistry

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Edited by F. Anne StephensonAllosteric modulators of pentameric ligand-gated ion channels are thought to act on elements of the pathways that couple agonist binding to channel gating. Using ␣4␤2 nicotinic acetylcholine receptors and the ␣4␤2-selective positive modulators 17␤-estradiol (␤EST) and desformylflustrabromine (dFBr), we have identified pathways that link the binding sites for these modulators to the Cys loop, a region that is critical for channel gating in all pentameric ligand-gated ion channels. Previous studies have shown that the binding site for potentiating ␤EST is in the C-terminal (post-M4) region of the ␣4 subunit. Here, using homology modeling in combination with mutagenesis and electrophysiology, we identified the binding site for potentiating dFBr on the top half of a cavity between the third (M3) and fourth transmembrane (M4) ␣-helices of the ␣4 subunit. We found that the binding sites for ␤EST and dFBr communicate with the Cys loop, through interactions between the last residue of post-M4 and Phe 170 of the conserved FPF sequence of the Cys loop, and that these interactions affect potentiating efficacy. In addition, interactions between a residue in M3 (Tyr 309 ) and Phe 167 , a residue adjacent to the Cys loop FPF motif, also affect dFBr potentiating efficacy. Thus, the Cys loop acts as a key control element in the allosteric transduction pathway for potentiating ␤EST and dFBr. Overall, we propose that positive allosteric modulators that bind the M3-M4 cavity or post-M4 region increase the efficacy of channel gating through interactions with the Cys loop.The ␣4␤2 nicotinic acetylcholine receptor (nAChR) 2 belongs to the superfamily of pentameric ligand-gated ion channels (pLGICs). In humans, this superfamily comprises the Cys loop receptors (including muscle and neuronal nAChRs, 5-HT 3 , GABA A , and glycine receptors), which mediate all fast central nervous system synaptic inhibition and much of fast peripheral excitation. Cys loop receptor subunits assemble as a pentamer of identical (homomeric channels) or different (heteromeric channels) subunits around a central ion channel. The individual subunits have a large extracellular N-terminal domain (ECD) that consists of 10 ␤-strands (␤1-␤10) folded into a ␤-sandwich and a transmembrane domain (TMD) with four transmembrane ␣ helices (M1-M4) connected by linkers (M1-M2, M2-M3, and M3-M4), as well as intracellular domains and a highly variable extracellular C-terminal (post-M4) region (1). There are 2-5 neurotransmitter binding sites at subunit interfaces within the ECD, and these sites are functionally coupled to the transmembrane ion channel located ϳ50 Å away. In the nAChR, the subunit contributing the principal face of the agonist binding site (an ␣ subunit) couples agonist-triggered agonist binding site movements to channel gating (2, 3). The coupling is achieved at the ECD-TMD interface by a principal pathway that couples the pre-M1 region in the ECD to the M2-M3 linker through the ␤1-␤2 loop (4) and the canonical FPF motif of the ␤6-...

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Subunit-Dependent Modulation of Neuronal Nicotinic Receptors by Zinc

Cited by 72 publications

References 38 publications

Minimal Structural Rearrangement of the Cytoplasmic Pore during Activation of the 5-HT3A Receptor

Minimal Structural Rearrangement of the Cytoplasmic Pore during Activation of the 5-HT3A Receptor

Combined actions of zinc and fluoxetine on nicotinic acetylcholine receptors

Role of the Cys Loop and Transmembrane Domain in the Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors

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