Substituted 2-Aminopyrimidines Selective for α7-Nicotinic Acetylcholine Receptor Activation and Association with Acetylcholine Binding Proteins

2017 ◽  
Vol 139 (10) ◽  
pp. 3676-3684 ◽  
Author(s):  
Katarzyna Kaczanowska ◽  
Gisela Andrea Camacho Hernandez ◽  
Larissa Bendiks ◽  
Larissa Kohs ◽  
Jose Manuel Cornejo-Bravo ◽  
...  
Keyword(s):  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Binding Proteins ◽  
Receptor Activation ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Acetylcholine Binding Proteins

scholarly journals Cynandione A alleviates neuropathic pain through spinal microglial interleukin-10/β-endorphin expression following α7 nicotinic acetylcholine receptor activation

2020 ◽  
Author(s):  
Qiao-Qiao Han ◽  
Min Yin ◽  
Zi-Ying Wang ◽  
Hao Liu ◽  
Jun-Ping Ao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
Receptor Activation ◽  
Primary Microglia ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
Α7 Nachr

Abstract Background Cynandione A, an acetophenone isolated from Cynanchum Wilfordii Radix, exhibits antihypersensitivity effects in neuropathic pain. This study sought to explore the target molecule and mechanisms underlying cynandione A mechanical antiallodynia, particularly related to the spinal glial expression of IL-10/β-endorphin, cAMP/PKA/p38/CREB signaling and α7 nicotinic acetylcholine receptor (α7 nAChR) activation. Methods IL-10 and β-endorphin in the spinal cord of spinal nerve ligation-induced neuropathic pain rats and cultured primary microglia were assessed by qRT-PCR and ELISA assays. Double immunofluorescence staining of IL-10, β-endorphin with glial and neuronal cellular biomarkers was also conducted in the spinal cord and cultured primary microglia. Microglial phosphorylation of PKA, p38, CREB and STAT3 were detected using western blot. Results Cynandione A significantly attenuated mechanical allodynia in neuropathic rats and substantially increased IL-10 and β-endorphin (but not dynorphin A) expression in the spinal cords and cultured primary microglia. The IL-10 antibody attenuated cynandione A-induced spinal or microglial gene expression of β-endorphin and mechanical antiallodynia, whereas the β-endorphin antiserum blocked cynandione A-induced mechanical antiallodynia but not spinal or microglial IL-10 gene expression. The α7 nAChR antagonist methyllycaconitine significantly declined cynandione A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. Cynandione A stimulated microglial phosphorylation of PKA, p38 and CREB, which was inhibited by methyllycaconitine. Treatment with the adenylyl cyclase inhibitor DDA, PKA inhibitor H-89, p38 inhibitor SB203580 and CREB inhibitor KG501 attenuated cynandione A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. Cynandione A stimulated spinal phosphorylation of the transcription factor STAT3, which was inhibited by methyllycaconitine, H-89 and the IL-10 antibody. The STAT3 inhibitor NSC74859 weakened cynandione A-induced mechanical antiallodynia and spinal expression of β-endorphin. Conclusion Our results illustrate that cynandione A produces mechanical antiallodynia through spinal microglial expression of IL-10 via the cAMP/PKA/p38/CREB signaling and subsequent β-endorphin expression via the IL-10/STAT3 signaling, following α7 nAChR activation.

scholarly journals In Silico Modeling of the α7 Nicotinic Acetylcholine Receptor: New Pharmacological Challenges Associated with Multiple Modes of Signaling

2020 ◽  
Vol 20 (10) ◽  
pp. 841-864 ◽  
Author(s):  
Alican Gulsevin ◽  
Roger L. Papke ◽  
Nicole Horenstein
Keyword(s):  
Ligand Binding ◽  
Acetylcholine Receptor ◽  
Nicotinic Acetylcholine Receptor ◽  
In Silico ◽  
Receptor Activation ◽  
Binding Studies ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
Nicotinic Acetylcholine ◽  
High Calcium ◽  
In Silico Studies

The α7 nicotinic acetylcholine receptor is a homopentameric ion-channel of the Cys-loop superfamily characterized by its low probability of opening, high calcium permeability, and rapid desensitization. The α7 receptor has been targeted for the treatment of the cognitive symptoms of schizophrenia, depression, and Alzheimer’s disease, but it is also involved in inflammatory modulation as a part of the cholinergic anti-inflammatory pathway. Despite its functional importance, in silico studies of the α7 receptor cannot produce a general model explaining the structural features of receptor activation, nor predict the mode of action for various ligand classes. Two particular problems in modeling the α7 nAChR are the absence of a high-resolution structure and the presence of five potentially nonequivalent orthosteric ligand binding sites. There is wide variability regarding the templates used for homology modeling, types of ligands investigated, simulation methods, and simulation times. However, a systematic survey focusing on the methodological similarities and differences in modeling α7 has not been done. In this work, we make a critical analysis of the modeling literature of α7 nAChR by comparing the findings of computational studies with each other and with experimental studies under the main topics of structural studies, ligand binding studies, and comparisons with other nAChR. In light of our findings, we also summarize current problems in the field and make suggestions for future studies concerning modeling of the α7 receptor.

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