Homomeric and Heteromeric α7 Nicotinic Acetylcholine Receptors in Health and Some Central Nervous System Diseases

Borroni, Virginia; Barrantes, Francisco J.

doi:10.3390/membranes11090664

Cited by 24 publications

(22 citation statements)

References 135 publications

(171 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since α7 subunits are identical unless manipulated, there is no easy way to determine any order in how the subunits come together to form the pentamer. (Note, however, that α7 subunits can assemble in heteromeric pentamers with β-subunits [ 102 , 103 ]). Cell surface α-bungarotoxin binding and electrophysiology are two methods showing that α7 pentamers are formed and inserted into the plasma membrane.…”

Section: Resultsmentioning

confidence: 99%

Speculation on How RIC-3 and Other Chaperones Facilitate α7 Nicotinic Receptor Folding and Assembly

Loring

2022

Molecules

View full text Add to dashboard Cite

The process of how multimeric transmembrane proteins fold and assemble in the endoplasmic reticulum is not well understood. The alpha7 nicotinic receptor (α7 nAChR) is a good model for multimeric protein assembly since it has at least two independent and specialized chaperones: Resistance to Inhibitors of Cholinesterase 3 (RIC-3) and Nicotinic Acetylcholine Receptor Regulator (NACHO). Recent cryo-EM and NMR data revealed structural features of α7 nAChRs. A ser-ala-pro (SAP) motif precedes a structurally important but unique “latch” helix in α7 nAChRs. A sampling of α7 sequences suggests the SAP motif is conserved from C. elegans to humans, but the latch sequence is only conserved in vertebrates. How RIC-3 and NACHO facilitate receptor subunits folding into their final pentameric configuration is not known. The artificial intelligence program AlphaFold2 recently predicted structures for NACHO and RIC-3. NACHO is highly conserved in sequence and structure across species, but RIC-3 is not. This review ponders how different intrinsically disordered RIC-3 isoforms from C. elegans to humans interact with α7 nAChR subunits despite having little sequence homology across RIC-3 species. Two models from the literature about how RIC-3 assists α7 nAChR assembly are evaluated considering recent structural information about the receptor and its chaperones.

show abstract

Section: Resultsmentioning

confidence: 99%

Speculation on How RIC-3 and Other Chaperones Facilitate α7 Nicotinic Receptor Folding and Assembly

Loring

2022

Molecules

View full text Add to dashboard Cite

show abstract

“…Agonist binding to α7 determines sufficient Na + influx-induced depolarization to activate VGCCs and Ca 2+ influx and lead to RyR-mediated CICR from the endoplasmic reticulum. In addition, the transition of α7 nAChRs to a high-affinity ligandbound desensitized state supports a metabotropic response marked by G protein activation of PLC, IP 3 production, and IP 3induced Ca 2+ release (Papke and Lindstrom, 2020;Borroni and Barrantes, 2021).…”

Section: Ionotropic and Metabotropic Nachr Signalingmentioning

confidence: 92%

“…They also showed that there is a nicotine-mediated increase in intracellular Ca 2+ that is due to α7 receptors (and probably α9-containing receptors, which are highly permeable to Ca 2+ and show increased mRNA expression in patient-derived xenograft GBM lines). In neurons, the time-course of nicotine and ACh activation of the homomeric α7 receptor is very fast (in the order of milliseconds; Papke and Lindstrom, 2020;Borroni and Barrantes, 2021), whereas in GBM cells nicotine activates Ca 2+ influx with a time-course of hundreds of seconds. This Ca 2+ signaling response persists longer than channel activation and may be the result of CICR from intra-cellular stores, as has been previously shown in the case of hippocampal astrocytes (Sharma and Vijayaraghavan, 2001).…”

Section: α9-containing Receptors In Gliomas and Glioblastomasmentioning

confidence: 99%

α9-Containing Nicotinic Receptors in Cancer

Pucci

Zoli

Clementi

et al. 2022

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Neuronal nicotinic acetylcholine receptors containing the α9 or the α9 and α10 subunits are expressed in various extra-neuronal tissues. Moreover, most cancer cells and tissues highly express α9-containing receptors, and a number of studies have shown that they are powerful regulators of responses that stimulate cancer processes such as proliferation, inhibition of apoptosis, and metastasis. It has also emerged that their modulation is a promising target for drug development. The aim of this review is to summarize recent data showing the involvement of these receptors in controlling the downstream signaling cascades involved in the promotion of cancer.

show abstract

“…Interestingly, the desensitization of α7-nAChR may be overcome by choline, a selective full agonist of such receptors. Therefore, the generation of choline by ACh hydrolysis may extend cholinergic signaling beyond the synaptic region after diffusion due to its long clearance, which may be relevant for AChEI therapy in AD (Borroni and Barrantes, 2021 ). The main elements of the cholinergic synapse are represented in Figure 2 .…”

Section: Introductionmentioning

confidence: 99%

Predictors of response to acetylcholinesterase inhibitors in dementia: A systematic review

et al. 2022

View full text Add to dashboard Cite

BackgroundThe mainstay of therapy for many neurodegenerative dementias still relies on acetylcholinesterase inhibitors (AChEI); however, there is debate on various aspects of such treatment. A huge body of literature exists on possible predictors of response, but a comprehensive review is lacking. Therefore, our aim is to perform a systematic review of the predictors of response to AChEI in neurodegenerative dementias, providing a categorization and interpretation of the results.MethodsWe conducted a systematic review of the literature up to December 31st, 2021, searching five different databases and registers, including studies on rivastigmine, donepezil, and galantamine, with clearly defined criteria for the diagnosis of dementia and the response to AChEI therapy. Records were identified through the string: predict*AND respon*AND (acetylcholinesterase inhibitors OR donepezil OR rivastigmine OR galantamine). The results were presented narratively.ResultsWe identified 1,994 records in five different databases; after exclusion of duplicates, title and abstract screening, and full-text retrieval, 122 studies were finally included.DiscussionThe studies show high heterogeneity in duration, response definition, drug dosage, and diagnostic criteria. Response to AChEI seems associated with correlates of cholinergic deficit (hallucinations, fluctuating cognition, substantia innominate atrophy) and preserved cholinergic neurons (faster alpha on REM sleep EEG, increased anterior frontal and parietal lobe perfusion after donepezil); white matter hyperintensities in the cholinergic pathways have shown inconsistent results. The K-variant of butyrylcholinesterase may correlate with better response in late stages of disease, while the role of polymorphisms in other genes involved in the cholinergic system is controversial. Factors related to drug availability may influence response; in particular, low serum albumin (for donepezil), CYP2D6 variants associated with reduced enzymatic activity and higher drug doses are the most consistent predictors, while AChEI concentration influence on clinical outcomes is debatable. Other predictors of response include faster disease progression, lower serum cholesterol, preserved medial temporal lobes, apathy, absence of concomitant diseases, and absence of antipsychotics. Short-term response may predict subsequent cognitive response, while higher education might correlate with short-term good response (months), and long-term poor response (years). Age, gender, baseline cognitive and functional levels, and APOE relationship with treatment outcome is controversial.

show abstract

Homomeric and Heteromeric α7 Nicotinic Acetylcholine Receptors in Health and Some Central Nervous System Diseases

Cited by 24 publications

References 135 publications

Speculation on How RIC-3 and Other Chaperones Facilitate α7 Nicotinic Receptor Folding and Assembly

Speculation on How RIC-3 and Other Chaperones Facilitate α7 Nicotinic Receptor Folding and Assembly

α9-Containing Nicotinic Receptors in Cancer

Predictors of response to acetylcholinesterase inhibitors in dementia: A systematic review

Contact Info

Product

Resources

About