Therapeutic Targeting of <i>α</i>7 Nicotinic Acetylcholine Receptors

Papke, Roger L.; Horenstein, Nicole A.

doi:10.1124/pharmrev.120.000097

Cited by 43 publications

(29 citation statements)

References 336 publications

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“…One of the most frequently sought-after goals in the pre-clinical developments on nicotinic drugs has been to identify drugs that will target α7 nAChR without affecting other subtypes like α4β2 receptors (Papke and Horenstein, 2021), leading to the identification of several α7-selective agonists. Among the first α7-selective agonists to be published, and one of the most widely used, is GTS-21 (DMXB) (de Fiebre et al, 1995), although even in the first publication it was noted to also antagonize α4β2 responses.…”

Section: α7-selective Agonistsmentioning

confidence: 99%

Insights Into the Differential Desensitization ofα4β2 Nicotinic Acetylcholine Receptor Isoforms Obtained With Positive Allosteric Modulation of Mutant Receptors

Papke

Stokes

2022

Mol Pharmacol

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Section: α7-selective Agonistsmentioning

confidence: 99%

Insights Into the Differential Desensitization ofα4β2 Nicotinic Acetylcholine Receptor Isoforms Obtained With Positive Allosteric Modulation of Mutant Receptors

Papke

Stokes

2022

Mol Pharmacol

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“…Emerging evidence indicates that α4β2, α7, and α9α10 nAChR subtypes are promising therapeutic targets for the management of chronic pain (Dineley et al, 2015;Papke and Lindstrom, 2020). In particular, α7 nAChR is one of the most abundant nAChR in the central nervous system and the peripheral system, as well as immune cells (Papke and Horenstein, 2021). Growing shreds of evidence indicate that potentiation of α7 nAChR is a novel therapeutic strategy for neurological diseases, including Alzheimer's diseases and Parkinson's diseases, schizophrenia, and traumatic brain injury (Kelso and Oestreich, 2012;Beinat et al, 2015;Quik et al, 2015;Ma and Qian, 2019).…”

Section: Introductionmentioning

confidence: 99%

Targeting α7 nicotinic acetylcholine receptors for chronic pain

Zhou

Liu²,

Liu³

et al. 2022

Front. Mol. Neurosci.

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Despite rapid advances in the field of chronic pain, it remains extremely challenging in the clinic. Pain treatment strategies have not improved for decades as opioids remain the main prescribed drugs for chronic pain management. However, long-term use of opioids often leads to detrimental side effects. Therefore, uncovering the mechanisms underlying the development and maintenance of chronic pain may aid the discovery of novel therapeutics to benefit patients with chronic pain. Substantial evidence indicates downregulation of α7 nicotinic acetylcholine receptors (α7 nAChR) in the sciatic nerve, dorsal root ganglia, and spinal cord dorsal horn in rodent models of chronic pain. Moreover, our recent study and results from other laboratories demonstrate that potentiation of α7 nAChR attenuates pain behaviors in various murine models of chronic pain. This review summarized and discussed the preclinical evidence demonstrating the therapeutic potential of α7 nAChR agonists and allosteric modulators in chronic pain. This evidence indicates that potentiation of α7 nAChR is beneficial in chronic pain, mostly by alleviating neuroinflammation. Overall, α7 nAChR-based therapy for chronic pain is an area with great promise, but more research regarding its detailed mechanisms is warranted.

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“…In many cell types, α7 nAChRs require specialized chaperones such as Resistance to Inhibitors of Cholinesterase 3 (RIC-3 [ 5 ]) or Transmembrane Protein 35A (TMEM35a, also known as Nicotinic Cholinergic Receptor Regulator or NACHO) [ 6 ] to properly fold and assemble. α7 nAChRs also show great therapeutic potential [ 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

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

Loring

2022

Molecules

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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.

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Therapeutic Targeting of α7 Nicotinic Acetylcholine Receptors

Cited by 43 publications

References 336 publications

Insights Into the Differential Desensitization ofα4β2 Nicotinic Acetylcholine Receptor Isoforms Obtained With Positive Allosteric Modulation of Mutant Receptors

Insights Into the Differential Desensitization ofα4β2 Nicotinic Acetylcholine Receptor Isoforms Obtained With Positive Allosteric Modulation of Mutant Receptors

Targeting α7 nicotinic acetylcholine receptors for chronic pain

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

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