Nicotinic Acetylcholine Receptors: Novel Targets for Neurological Diseases

A special issue of Brain Sciences (ISSN 2076-3425). This special issue belongs to the section "Molecular and Cellular Neuroscience".

Deadline for manuscript submissions: closed (25 February 2021) | Viewed by 4335

Special Issue Editor


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Guest Editor
Center for Sensory Neuroscience, Boys Town National Research Hospital, Omaha 68131, NE, USA
Interests: Nicotnicc acetylcholine receptors; brain development; neurodevelopmental disorders; sensory sytems

Special Issue Information

Dear Colleagues,

Nicotinic acetylcholine receptors (AChR)  play pivotal roles in the etiology of neurological disorders.  The most well-known example is the AChR at the skeletal muscle neuromuscular junction, in which auto-antibodies against AChR subunits are a major underlying cause of Myasthenia Gravis.   Although first reported in the 1970’s, Myasthenia Gravis remains a well-studied neurological disease and AChR remains a target for treatment.  The skeletal muscle AChR is also a target for treatment of Amyotrophic Lateral Sclerosis. Although the first AChR discovered, the subunits of the skeletal muscle AChR  (αβδε) are not the phylogenetically older subunits and are not the subunits typically associated with the mammalian central and other peripheral nervous systems (α2-7, 9-10, and β2-4).

The AChR subunits expressed at synaptic and non-synaptic sites throughout the body are also important therapeutic targets for several neurological disorders. For example, α7 is a potential therapeutic target for neurodevelopmental disorders, such as schizophrenia. α9 is a potential therapeutic target for glioblastoma. α6β2 is a therapeutic target for neurodegenerative diseases such as Parkinson’s. The α5α3β4 receptor is a target for nicotine dependence. Immune cells also express AChR subunits, and can affect neurological disorders, such as multiple sclerosis.

AChR make good therapeutic targets for neurological diseases because they are often modulatory and regulate the primary neurotransmitters glutamate or dopamine. In other instances, AChR gene duplication or deletion is causative in neurological disease. CHRNA7, for example, is an important gene in the 15q13.3 microdeletion syndrome. The α9 subunit is unique in that it is not expressed in normal brain, but may be expressed during migration and/or proliferation in glioblastoma.

In this topic section we will focus on novel therapies that target AChR, particularly in neurological disorders that are currently resistant to treatment.

Dr. Barbara J. Morley
Guest Editor

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Keywords

  • Nicotinic acetylcholine receptor
  • Therapeutic target
  • Neurological disorder
  • Autism
  • Addiction
  • Schizophrenia
  • Myasthenia Gravis
  • Amyotrophic Lateral Sclerosis
  • Glioblastoma
  • Multiple sclerosis

Published Papers (1 paper)

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20 pages, 858 KiB  
Review
Nicotinic Receptors in Sleep-Related Hypermotor Epilepsy: Pathophysiology and Pharmacology
by Andrea Becchetti, Laura Clara Grandi, Giulia Colombo, Simone Meneghini and Alida Amadeo
Brain Sci. 2020, 10(12), 907; https://doi.org/10.3390/brainsci10120907 - 25 Nov 2020
Cited by 16 | Viewed by 3944
Abstract
Sleep-related hypermotor epilepsy (SHE) is characterized by hyperkinetic focal seizures, mainly arising in the neocortex during non-rapid eye movements (NREM) sleep. The familial form is autosomal dominant SHE (ADSHE), which can be caused by mutations in genes encoding subunits of the neuronal nicotinic [...] Read more.
Sleep-related hypermotor epilepsy (SHE) is characterized by hyperkinetic focal seizures, mainly arising in the neocortex during non-rapid eye movements (NREM) sleep. The familial form is autosomal dominant SHE (ADSHE), which can be caused by mutations in genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR), Na+-gated K+ channels, as well as non-channel signaling proteins, such as components of the gap activity toward rags 1 (GATOR1) macromolecular complex. The causative genes may have different roles in developing and mature brains. Under this respect, nicotinic receptors are paradigmatic, as different pathophysiological roles are exerted by distinct nAChR subunits in adult and developing brains. The widest evidence concerns α4 and β2 subunits. These participate in heteromeric nAChRs that are major modulators of excitability in mature neocortical circuits as well as regulate postnatal synaptogenesis. However, growing evidence implicates mutant α2 subunits in ADSHE, which poses interpretive difficulties as very little is known about the function of α2-containing (α2*) nAChRs in the human brain. Planning rational therapy must consider that pharmacological treatment could have different effects on synaptic maturation and adult excitability. We discuss recent attempts towards precision medicine in the mature brain and possible approaches to target developmental stages. These issues have general relevance in epilepsy treatment, as the pathogenesis of genetic epilepsies is increasingly recognized to involve developmental alterations. Full article
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