![finetunes meaning finetunes meaning](https://i.ytimg.com/vi/fMn0RvVq4oY/maxresdefault.jpg)
The metabotropic responses triggered upon receptor activation depend on cell-specific protein-α7 receptor interactions that are mainly mediated through the α7-ICD. In some non-neuronal cells, signaling pathways elicited by activation of α7 have been shown to be independent of its activity as an ion channel. Its activation induces the release of calcium from intracellular stores and triggers several signal transduction cascades, including JAK2/STAT3 and PI3K/Akt pathways, activation of Ca 2+-calmodulin-dependent protein kinase and MAPK/ERK pathway. In addition to its ionotropic actions, α7 shows important metabotropic activity. The hallmarks of its ionotropic activity are rapid kinetics, rapid desensitization, and high calcium permeability. Α7 responds to acetylcholine (ACh) by opening an intrinsic cationic channel which triggers rapid membrane depolarization and calcium influx. Α7 belongs to the family of pentameric ligand-gated ion channels that contain an extracellular domain (ECD), which carries the agonist binding sites a transmembrane domain (TMD), which forms the ion pore and the gate and an intracellular domain (ICD), which contains sites for modulation and intracellular signaling. On the other hand, increased α7 activity in certain cells may contribute to cancer progression via the promotion of cell proliferation, apoptosis inhibition and tumor angiogenesis stimulation. Moreover, α7 has been recently proposed to be involved in some clinical manifestations of COVID-19. Potentiation of α7 has therefore emerged as a therapeutic strategy for neurological, neurodegenerative and inflammatory disorders. α7 is also expressed in non-neuronal cells, such as astrocytes, microglia, oligodendrocytes, endothelial cells, and immune cells, where it has anti-inflammatory and neuroprotective activities. α7 reduced activity has been associated with several neurological and neurodegenerative disorders, particularly schizophrenia and Alzheimer’s disease.
![finetunes meaning finetunes meaning](https://www.monkshillbooks.co.uk/images/prod/fallacy_of_fine_tuning2_400.jpg)
In neurons, α7 receptors are found at presynaptic locations where they facilitate the release of neurotransmitters at postsynaptic locations where they mediate fast synaptic transmission, and at perisynaptic locations where they modulate neuronal excitability and activate a variety of signaling pathways through volume transmission. The α7 nicotinic acetylcholine receptor (nAChR) is highly expressed in the brain, mainly in the cortex, hippocampus, and subcortical limbic regions, where it contributes to cognition, attention, and working memory. Overall, phosphorylation/dephosphorylation events fine-tune the integrated cell response mediated by α7 activation, thus having a broad impact on α7 cholinergic signaling.
![finetunes meaning finetunes meaning](https://restitutio.org/wp-content/uploads/2016/10/fine-tuning.png)
Thus, while tyrosine phosphorylation is absolutely required for α7-triggered ERK pathway, it negatively modulates α7 ionotropic activity. However, the mutant receptor is incapable of triggering ERK1/2 phosphorylation in response to the α7-agonist. The tyrosine-free mutant receptor shows longer duration-activation episodes, reduced desensitization rate and significantly faster recovery from desensitization, indicating that phosphorylation decreases α7 channel activity by favoring the desensitized state. Removal of two tyrosine residues at the α7 intracellular domain recapitulates the effects mediated by tyrosine kinase inhibition. The reduction of phosphorylation by tyrosine kinase inhibition increases the duration and frequency of activation episodes, whereas the inhibition of phosphatases has the opposite effect. α7 single-channel activity elicited by ACh appears as brief isolated openings and less often as episodes of few openings in quick succession. As protein phosphorylation is an important cell function regulatory mechanism, deciphering how tyrosine phosphorylation modulates α7 dual ionotropic/metabotropic molecular function is required for understanding its integral role in physiological and pathological processes.
![finetunes meaning finetunes meaning](https://i.ytimg.com/vi/G8AMLgK7f1c/maxresdefault.jpg)
It operates both as a ligand-gated cationic channel and as a metabotropic receptor in neuronal and non-neuronal cells. The α7 nicotinic acetylcholine receptor is involved in neurological, neurodegenerative, and inflammatory disorders.