Review
Nicotinic ACh receptors as therapeutic targets in CNS disorders

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Highlights

The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability by acting on the cys-loop cation-conducting ligand-gated nicotinic ACh receptor (nAChR) channels. These receptors are widely distributed throughout the central nervous system (CNS), being expressed on neurons and non-neuronal cells, where they participate in a variety of physiological responses such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and cognitive functions. In the mammalian brain, nine different subunits have been found thus far, which assemble into pentameric complexes with much subunit diversity; however, the α7 and α4β2 subtypes predominate in the CNS. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders. Here we will briefly discuss the functional makeup and expression of the nAChRs in mammalian brain, and their role as targets in neurodegenerative diseases (in particular Alzheimer's disease, AD), neurodevelopmental disorders (in particular autism and schizophrenia), and neuropathic pain.

Section snippets

Functional role of nAChRs in the brain

The nAChRs belong to the superfamily of cys-loop receptors (Figure 1), which also includes the serotonin 5-HT3, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (GABA)A, GABAC, and glycine receptors, and participate in a variety of physiological functions, including the regulation of neuronal excitability and neurotransmitter release 1, 2, 3, 4. The nAChRs are widely distributed throughout the peripheral nervous system (PMS) and the CNS, as well as the immune system and various peripheral

AD

Neuronal nAChR dysfunction is involved in the pathophysiology of various neurodegenerative diseases, including AD and Parkinson's disease (PD). Here we will focus solely on AD since there are excellent recent reviews discussing the complexity between nAChR distribution within the nigro-striatal pathway, how nAChR function contribute to this network, and PD pathophysiology [53].

Neurodevelopmental disorders

The nAChRs are widely expressed on both differentiated and undifferentiated CNS cells, and are known to influence development and modulate multiple pathways of neurogenesis during brain development 114, 115. Here we discuss the role of nAChRs in two of the most common neurodevelopmental disorders, autism and schizophrenia.

Pain

Pain is an unpleasant sensory feeling that includes neuropathic, nociceptive, and psychogenic pain [148]. If the pain persists for longer than a few months, the condition is said to be chronic (as opposed to acute) pain [149]. The most common reason for neuropathic pain is a disruption in the normal functioning of the somatosensory system [150]. The nAChRs have been known for some time to be involved in the process of mediating pain, and as such the analgesic effects of nAChR agonists as well

Concluding remarks

The distribution of nAChRs in the nervous system is extensive yet discrete, and historically this has made them an active target of drug development for treating neurodegenerative diseases such as AD. However, the nAChRs are increasingly appreciated for their roles in neurodevelopment and sensory processing, and thus have been identified as therapeutic targets in autism, schizophrenia, and neuropathic pain. Unfortunately, no nAChR compounds have demonstrated disease-modifying properties for any

Acknowledgments

This work was supported by the Intramural Research Program, NIEHS/NIH to J.L.Y. and A.A.P., a kind gift to K.T.D. from J&W Mohn, and an Independent Investigator Research Grant from the Alzheimer's Association to K.T.D.

References (195)

  • Z. Gu et al.

    Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity

    Neuron

    (2011)
  • M. Alkondon

    alpha-bungarotoxin- and methyllycaconitine-sensitive nicotinic receptors mediate fast synaptic transmission in interneurons of rat hippocampal slices

    Brain Res.

    (1998)
  • K.A. Bell

    Nicotinic excitatory postsynaptic potentials in hippocampal CA1 interneurons are predominantly mediated by nicotinic receptors that contain alpha4 and beta2 subunits

    Neuropharmacology

    (2011)
  • D.S. Auld

    Alzheimer's disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies

    Progr. Neurobiol.

    (2002)
  • E.D. Levin

    Complex relationships of nicotinic receptor actions and cognitive functions

    Biochem. Pharmacol.

    (2013)
  • H.R. Parri

    Research update: Alpha7 nicotinic acetylcholine receptor mechanisms in Alzheimer's disease

    Biochem. Pharmacol.

    (2011)
  • J. Court

    Nicotinic receptor abnormalities in Alzheimer's disease

    Biol. Psychiatry

    (2001)
  • P. Davies et al.

    Postmortem stability of alpha-bungarotoxin binding sites in mouse and human brain

    Brain Res.

    (1981)
  • B.T. Hyman

    National Institute on Aging–Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease

    Alzheimers Dement.

    (2012)
  • M.S. Albert

    The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

    Alzheimers Dement.

    (2011)
  • G.M. McKhann

    The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging–Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

    Alzheimers Dement.

    (2011)
  • K.T. Dineley

    beta-Amyloid peptide activates alpha 7 nicotinic acetylcholine receptors expressed in Xenopus oocytes

    J. Biol. Chem.

    (2002)
  • W.F. Yu

    High selective expression of alpha7 nicotinic receptors on astrocytes in the brains of patients with sporadic Alzheimer's disease and patients carrying Swedish APP 670/671 mutation: a possible association with neuritic plaques

    Exp. Neurol.

    (2005)
  • K.T. Dineley

    Accelerated plaque accumulation, associative learning deficits, and up-regulation of alpha 7 nicotinic receptor protein in transgenic mice co-expressing mutant human presenilin 1 and amyloid precursor proteins

    J. Biol. Chem.

    (2002)
  • H.Y. Wang

    S 24795 limits beta-amyloid-alpha7 nicotinic receptor interaction and reduces Alzheimer's disease-like pathologies

    Biol. Psychiatry

    (2010)
  • J.L. Yakel

    Gating of nicotinic ACh receptors: latest insights into ligand binding and function

    J. Physiol.

    (2010)
  • E.A. Gay et al.

    Gating of nicotinic ACh receptors; new insights into structural transitions triggered by agonist binding that induce channel opening

    J. Physiol.

    (2007)
  • J.A. Dani et al.

    Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system

    Annu. Rev. Pharmacol. Toxicol.

    (2007)
  • E.X. Albuquerque

    Mammalian nicotinic acetylcholine receptors: from structure to function

    Physiol. Rev.

    (2009)
  • P. Seguela

    Molecular cloning, functional properties, and distribution of rat brain alpha 7: a nicotinic cation channel highly permeable to calcium

    J. Neurosci.

    (1993)
  • F. Rubboli

    Distribution of nicotinic receptors in the human hippocampus and thalamus

    Eur. J. Neurosci.

    (1994)
  • J. Drago

    Neuronal nicotinic receptors: insights gained from gene knockout and knockin mutant mice

    Cell. Mol. Life Sci.

    (2003)
  • E. Dominguez del Toro

    Immunocytochemical localization of the alpha 7 subunit of the nicotinic acetylcholine receptor in the rat central nervous system

    J. Comp. Neurol.

    (1994)
  • J.L. Yakel

    Cholinergic receptors: functional role of nicotinic ACh receptors in brain circuits and disease

    Pflugers Arch.

    (2013)
  • S. Jones et al.

    Functional nicotinic ACh receptors on interneurones in the rat hippocampus

    J. Physiol.

    (1997)
  • S.S. Khiroug

    Rat nicotinic ACh receptor alpha7 and beta2 subunits co-assemble to form functional heteromeric nicotinic receptor channels

    J. Physiol.

    (2002)
  • S.N. Sudweeks et al.

    Functional and molecular characterization of neuronal nicotinic ACh receptors in rat CA1 hippocampal neurons

    J. Physiol.

    (2000)
  • N.S. Millar et al.

    Assembly and trafficking of nicotinic acetylcholine receptors (Review)

    Mol. Membr. Biol.

    (2008)
  • H. Wang

    Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation

    Nature

    (2003)
  • I. Wessler et al.

    Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans

    Br. J. Pharmacol.

    (2008)
  • J.X. Shen et al.

    Functional alpha7 nicotinic ACh receptors on astrocytes in rat hippocampal CA1 slices

    J. Mol. Neurosci.

    (2012)
  • G. Sharma et al.

    Nicotinic cholinergic signaling in hippocampal astrocytes involves calcium-induced calcium release from intracellular stores

    Proc. Natl. Acad. Sci. U.S.A.

    (2001)
  • R.D. Shytle

    Cholinergic modulation of microglial activation by alpha 7 nicotinic receptors

    J. Neurochem.

    (2004)
  • M.L. Si et al.

    Alpha7-nicotinic acetylcholine receptors on cerebral perivascular sympathetic nerves mediate choline-induced nitrergic neurogenic vasodilation

    Circ. Res.

    (2002)
  • E.D. Levin

    alpha7-Nicotinic receptors and cognition

    Curr. Drug Targets

    (2012)
  • M. Velez-Fort

    Functional alpha 7-containing nicotinic receptors of NG2-expressing cells in the hippocampus

    Glia

    (2009)
  • R. De Simone

    Activation of alpha7 nicotinic acetylcholine receptor by nicotine selectively up-regulates cyclooxygenase-2 and prostaglandin E2 in rat microglial cultures

    J. Neuroinflammation

    (2005)
  • T. Suzuki

    Microglial alpha7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role

    J. Neurosci. Res.

    (2006)
  • B.T. Hawkins

    Modulation of cerebral microvascular permeability by endothelial nicotinic acetylcholine receptors

    Am. J. Physiol. Heart Circ. Physiol.

    (2005)
  • C.M. Hernandez et al.

    alpha7 nicotinic acetylcholine receptors in Alzheimer's disease: neuroprotective, neurotrophic or both?

    Curr. Drug Targets

    (2012)
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