scholarly journals Structure and Activity of α-Conotoxin PeIA at Nicotinic Acetylcholine Receptor Subtypes and GABAB Receptor-coupled N-type Calcium Channels

2011 ◽  
Vol 286 (12) ◽  
pp. 10233-10237 ◽  
Author(s):  
Norelle L. Daly ◽  
Brid Callaghan ◽  
Richard J. Clark ◽  
Simon T. Nevin ◽  
David J. Adams ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Analgesic Activity ◽  
Gabab Receptor ◽  
Fold Increase ◽  
Receptor Activation ◽  
Receptor Subtypes ◽  
Nicotinic Acetylcholine ◽  
Diverse Range

α-Conotoxins are peptides from cone snails that target the nicotinic acetylcholine receptor (nAChR). RgIA and Vc1.1 have analgesic activity in animal pain models. Both peptides target the α9α10 nAChR and inhibit N-type calcium channels via GABAB receptor activation, but the mechanism of action of analgesic activity is unknown. PeIA has previously been shown to inhibit the α9α10 and α3β2 nAChRs. In this study, we have determined the structure of PeIA and shown that it is also a potent inhibitor of N-type calcium channels via GABAB receptor activation. The characteristic α-conotoxin fold is present in PeIA, but it has a different distribution of surface-exposed hydrophobic and charged residues compared with Vc1.1. Thus, the surface residue distribution, rather than the overall fold, appears to be responsible for the 50-fold increase in selectivity at the α3β2 nAChR by PeIA relative to Vc1.1. In contrast to their difference in potency at the nAChR, the equipotent activity of PeIA and Vc1.1 at the GABAB receptor suggests that the GABAB receptor is more tolerant to changes in surface residues than is the nAChR. The conserved Asp-Pro-Arg motif of Vc1.1 and RgIA, which is crucial for potency at the α9α10 nAChR, is not required for activity at GABAB receptor/N-type calcium channels because PeIA has a His-Pro-Ala motif in the equivalent position. This study shows that different structure-activity relationships are associated with the targeting of the GABAB receptor versus nAChRs. Furthermore, there is probably a much more diverse range of conotoxins that target the GABAB receptor than currently realized.

scholarly journals Firing responses mediated via distinct nicotinic acetylcholine receptor subtypes in rat prepositus hypoglossi nuclei neurons

2018 ◽  
Vol 120 (4) ◽  
pp. 1525-1533
Author(s):  
Yue Zhang ◽  
Yuchio Yanagawa ◽  
Yasuhiko Saito
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Firing Frequency ◽  
Membrane Properties ◽  
Receptor Subtypes ◽  
Nicotinic Acetylcholine ◽  
Firing Patterns ◽  
Prepositus Hypoglossi ◽  
Specific Antagonist ◽  
The Relationship

We previously reported that cholinergic current responses mediated via nicotinic acetylcholine (ACh) receptors (nAChRs) in the prepositus hypoglossi nucleus (PHN), which participates in gaze control, can be classified into distinct types based on different kinetics and are mainly composed of α7- and/or non-α7-subtypes: fast (F)-, slow (S)-, and fast and slow (FS)-type currents. In this study, to clarify how each current type is related to neuronal activities, we investigated the relationship between the current types and the membrane properties and the firing responses that were induced by each current type. The proportion of the current types differed in neurons that exhibited different afterhyperpolarization (AHP) profiles and firing patterns, suggesting that PHN neurons show a preference for specific current types dependent on the membrane properties. In response to ACh, F-type neurons showed either one action potential (AP) or multiple APs with a short firing duration, and S-type neurons showed multiple APs with a long firing duration. The firing frequency of F-type neurons was significantly higher than that of S-type and FS-type neurons. An α7-subtype-specific antagonist abolished the firing responses of F-type neurons and reduced the responses of FS-type neurons but had little effect on the responses of S-type neurons, which were reduced by a non-α7-subtype-specific antagonist. These results suggest that the different properties of the current types and the distinct expression of the nAChR subtypes in PHN neurons with different membrane properties produce unique firing responses via the activation of nAChRs. NEW & NOTEWORTHY Prepositus hypoglossi nucleus (PHN) neurons show distinct nicotinic acetylcholine receptor (nAChR)-mediated current responses. The proportion of the current types differed in the neurons that exhibited different afterhyperpolarization profiles and firing patterns. The nAChR-mediated currents with different kinetics induced firing responses of the neurons that were distinct in the firing frequency and duration. These results suggest that the different properties of the current types in PHN neurons with different membrane properties produce unique firing responses via the activation of nAChRs.

Expression of nicotinic acetylcholine receptor subtypes in brain and retina

1991 ◽  
Vol 10 (1) ◽  
pp. 61-70 ◽  
Author(s):  
P.J. Whiting ◽  
R. Schoepfer ◽  
W.G. Conroy ◽  
M.J. Gore ◽  
K.T. Keyser ◽  
...  
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Receptor Subtypes ◽  
Nicotinic Acetylcholine

scholarly journals IN SILICO DESIGN AND MOLECULAR DOCKING STUDIES OF SOME 1, 2-BENZISOXAZOLE DERIVATIVES FOR THEIR ANALGESIC AND ANTI-INFLAMMATORY ACTIVITY

2017 ◽  
Vol 9 (3) ◽  
pp. 133
Author(s):  
Sarath Sasi Kumar ◽  
Anjali T
Keyword(s):  
Molecular Docking ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Analgesic Activity ◽  
In Silico ◽  
Docking Studies ◽  
Inflammatory Activity ◽  
Nicotinic Acetylcholine ◽  
Cox 2 ◽  
Anti Inflammatory

Objective: In silico design and molecular docking of 1,2-benzisoxazole derivatives for their analgesic and anti-inflammatory activity using computational methods.Methods: In silico molecular properties of 1,2-benzisoxazole derivatives were predicted using various software’s such as Chemsketch, Molinspiration, PASS and Schrodinger to select compounds having optimum drug-likeness, molecular descriptors resembling those of standard drugs and not violating the ‘Lipinski rule of 5’. Molecular docking was performed on active site of nicotinic acetylcholine receptor (PDB: 2KSR) for analgesic activity and COX-2 (PDB: 6COX) for anti-inflammatory activity using Schrodinger under maestro molecular modelling environment.Results: From the results of molecular docking studies of 1,2-benzisoxazole derivatives, all the compounds showed good binding interactions with Nicotinic acetylcholine receptor and COX-2. Compounds 4a and 4c showed highest binding scores (-7.46 and-7.21 respectively) with nicotinic acetylcholine receptor and exhibited maximum analgesic activity. Compound 4a showed highest binding score (-7.8) with COX-2 and exhibited maximum anti-inflammatory activity.Conclusion: All the derivatives of 1,2-benzisoxazole showed good analgesic and anti-inflammatory activity as predicted using molecular docking on respective receptors.

scholarly journals Inhibition of Neuronal Nicotinic Acetylcholine Receptor Subtypes by α-Conotoxin GID and Analogues

2008 ◽  
Vol 284 (8) ◽  
pp. 4944-4951 ◽  
Author(s):  
Emma L. Millard ◽  
Simon T. Nevin ◽  
Marion L. Loughnan ◽  
Annette Nicke ◽  
Richard J. Clark ◽  
...  
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Neuronal Nicotinic Acetylcholine Receptor ◽  
Receptor Subtypes ◽  
Nicotinic Acetylcholine

scholarly journals Chemical tuning of photoswitchable azobenzenes: a photopharmacological case study using nicotinic transmission

2019 ◽  
Vol 15 ◽  
pp. 2812-2821 ◽  
Author(s):  
Lorenzo Sansalone ◽  
Jun Zhao ◽  
Matthew T Richers ◽  
Graham C R Ellis-Davies
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Brain Slices ◽  
Green Light ◽  
Receptor Activation ◽  
Great Promise ◽  
Synthetic Approach ◽  
Absorption Bands ◽  
Nicotinic Acetylcholine ◽  
Biological Studies

We have developed photochromic probes for the nicotinic acetylcholine receptor that exploit the unique chemical properties of the tetrafluoroazobenzene (4FAB) scaffold. Ultraviolet light switching and rapid thermal relaxation of the metastable cis configuration are the main drawbacks associated with standard AB-based switches. We designed our photoprobes to take advantage of the excellent thermodynamic stability of the cis-4FAB configuration (thermal half-life > 12 days at 37 °C in physiological buffer) and cis–trans photostationary states above 84%. Furthermore, the well-separated n–π* absorption bands of trans- and cis-4FAB allow facile photoswitching with visible light in two optical channels. A convergent 11-step synthetic approach allowed the installation of a trimethylammonium (TA) head onto the 4FAB scaffold, by means of an alkyl spacer, to afford a free diffusible 4FABTA probe. TAs are known to agonize nicotinic receptors, so 4FABTA was tested on mouse brain slices and enabled reversible receptor activation with cycles of violet and green light. Due to the very long-lived metastable cis configuration, 4FAB in vivo use could be of great promise for long term biological studies. Further chemical functionalization of this 4FAB probe with a maleimide functionality allowed clean cross-linking with glutathione. However, attempts to conjugate with a cysteine on a genetically modified nicotinic acetylcholine receptor did not afford the expected light-responsive channel. Our data indicate that the 4FAB photoswitch can be derivatized bifunctionally for genetically-targeted photopharmacology whilst preserving all the favorable photophysical properties of the parent 4FAB scaffold, however, the tetrafluoro motif can significantly perturb pharmacophore–protein interactions. In contrast, we found that the freely diffusible 4FABTA probe could be pre-set with green light into an OFF state that was biologically inert, irradiation with violet light effectively "uncaged" agonist activity, but in a photoreversible manner. Since the neurotransmitter acetylcholine has fully saturated heteroatom valences, our photoswitchable 4FABTA probe could be useful for physiological studies of this neurotransmitter.

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