PubMed: 17009926

Title
Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system.
Journal
Annual review of pharmacology and toxicology
Volume
47
Issue
None
Pages
699-729
Date
2007-01-01
Authors
Bertrand D | Dani JA

Evidence 9b88b3a7c6

Ivermectin is an example of a positive allosteric effector that modifies the pharmacological profile of the α7 nAChR.

Evidence 245fc4302c

Activation and desensitization of nAChRs by bath-applied nicotine also increases LTD induced by a stimulus train

Evidence b7bb57d804

The nicotine initially activates nAChRs on DA neurons, causing an increase in burst firing and overall firing rate (88, 121, 123, 124, 134).

Evidence 8ea0831b0c

Results show that genistein does not alter the surface expression of nAChRs, but rather it modifies nAChRs in the cell membrane (71).

Evidence 502566d5f7

Another allosteric effector, 1-(5-chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea (PNU-120596), dramatically modifies the response time course, ampliude of the current, and agonist sensitivity of the rat and human α7 nAChRs (70).

Evidence 5c46381633

The most commonly prescribed treatments for AD are acetylcholinesterase inhibitors, which decrease the hydrolysis rate of ACh and, thereby, enhance cholinergic signaling. One such drug, galantamine (Reminyl), also potentiates nAChRs (66).

Evidence 3b30b53f16

Although Aβ peptides negatively alter the cholinergic system at multiple sites, including ACh synthesis, ACh release, and muscarinic receptors (157), the discovery that Aβ1−42 binds to α7 nAChRs with high affinity suggested the potential for a causal role of nAChRs in AD (159, 160).

Evidence fe04459aac

This prospect was supported by the finding that α7 nAChRs were found in plaques (159), and α7 and α4 subunits positively correlated with neurons that accumulated Aβ and hyperphosphorylated tau in AD brain tissue (161).

Evidence 35d8324899

This calcium influx can trigger calcium-induced calcium release from intracellular stores (86).

Evidence 5c6853e618

For example, local infusion of the α7 antagonist, methyllycaconitine (MLA), or the β2∗ antagonist, dihydro-β-erythroidine (DHβE), into the basolateral amygdala, the ventral hippocampus, or the dorsal hippocampus impairs the working memory of rats seeking food reward within a 16-arm radial maze (146–148).

Evidence 4d4e70c900

The combination of enhanced glutamatergic release and strong postsynaptic response produces LTP of the glutamatergic afferents.

Evidence ed8efa06c7

Exogenously applied nicotinic agonists enhance and nicotinic antagonists often diminish the release of ACh, dopamine (DA), norepinephrine, and serotonin, as well as glutamate and GABA.

Evidence 8a002ab12a

In general, nicotinic agonists improve certain forms of memory, and nicotinic antagonists and cholinergic lesions impair memory (5, 141–145).

Evidence 51e6bf3da9

In animal studies, acute and chronic nicotine administration improves working memory, and nicotinic agonists were found to improve learning and memory in humans and nonhuman primates (145).

Evidence 8779c6a4fb

During attention tasks, the nicotinic antagonist, mecamylamine, impaired accuracy or reaction time (151, 152) and nicotinic agonists improved accuracy (153).

Evidence 290707e19c

Consistent with these treatments, nicotinic agents improve cognitive deficits of AD patients (20, 158).

Evidence 421ffd078a

Unlike many neurotransmitter signals that are shaped by pumps that return the transmitter to the intracellular space, the spread of ACh from the release site is determined by diffusion and by acetylcholinesterase (AChE) hydrolysis of ACh.

Evidence 77aeb86dd8

The α7 nAChR has a relatively low affinity for ACh activation, with an effective dose for half-activation at approximately 200 μM ACh.

Evidence 354d7c1728

In most cases, the exogenously applied ACh caused action potential firing by the GABA neuron that consequently regulated the activity of nearby pyramidal neurons (100, 103).

Evidence 6b36d04cfb

Another important aspect of this diffusive ACh signal is that its eventual hydrolysis creates choline, which also activates and desensitizes nAChRs in a subtype-selective manner (54, 55).

Evidence 806838959b

Dephosphorylation of the α7 receptor by genistein causes a significant increase of ACh-evoked responses without modifying the response time course or ACh sensitivity (71, 72).

Evidence 1253e236c2

Nicotine decreases tonic DA release in the striatum that is evoked by single action potentials (127), and nicotine also alters the frequency dependence of DA release that is electrically evoked by stimulus trains (130, 131).

Evidence b370d97b5f

Simultaneously, nicotine activates presynaptic α7∗ nAChRs, boosting glutamatergic synaptic transmission onto DA neurons (23, 88, 123, 134).

Evidence 7dc3c760e8

Moreover, although nicotine increases wakefulness in wild-type mice, it does not affect β2−/− mice. Overall, stimulation of nAChRs promotes arousal and REM sleep.

Evidence a1ae332902

This effect of preterminal nAChRs is inhibited by tetrodotoxin, which blocks sodium channels and, thus, prevents the regenerative voltage-dependent activation of calcium channels in the presynaptic bouton.

Evidence 571197f169

Postsynaptic β2∗ nAChRs initially depolarize DA neurons, causing them to fire action potentials while presynaptic α7∗ nAChRs boost glutamate release.

Evidence 3dcb010d03

By modulating activity-dependent events, nAChRs participate in fundamental aspects of synaptic plasticity that are involved in attention, learning, memory, and development (3, 12–16).

Evidence 96a8ed2807

In addition, nAChR activity produces a depolarization that activates voltage-gated calcium channels in the presynaptic terminal (87).

Evidence 8e0c5a2f31

The most well-appreciated neuronal loss, however, is in the cholinergic system (155, 156), particularly the basal forebrain cholinergic system comprised of the medial septal nucleus, the horizontal and vertical diagonal bands of Broca, and the nucleus basalis of Meynert (157).

Evidence 5ab80f8551

As AD worsens, cholinergic neurons are progressively lost and the number of nAChRs declines, particularly in the hippocampus and cortex (140, 158).

Evidence 89edf2b4e1

Acting through these excitatory and inhibitory inputs and nAChRs located on the DA neurons, nicotinic receptors influence the firing modes and firing frequency of DA neurons (119, 121).

Evidence a39a9ad5a0

Nicotinic receptors also modulate glutamatergic synaptic plasticity.

Evidence c354f6ff62

Genetic evidence has linked nicotinic receptors to epilepsy and schizophrenia, and studies with mutant mice have implicated nAChRs in pain mechanisms, anxiety, and depression.

Evidence 2a33bff11f

Cholinergic volume transmission enables ACh to diffuse and to act at lower concentrations some distance away from the release site.

Evidence c725e6f435

In the rat CA3 region, spontaneous activation of GABA A receptors produces giant depolarizing potentials, whose frequency is controlled by α7∗ and non-α7 nAChRs.

Evidence c0e4ae62e8

In some cases, the highly calcium-permeable α7-containing (α7∗) nAChRs mediate the increased release of neurotransmitter, but in other cases different nAChR subtypes are involved.

Evidence 25976d6703

Preterminal nAChRs located before the presynaptic terminal bouton indirectly affect neurotransmitter release by activating voltage-gated channels and, potentially, initiating action potentials (78, 91, 93).

Evidence 313d8fff7f

Dimethylphenylpiperazidium (DMPP) normally is a partial agonist at this receptor subtype, but it becomes almost a full agonist following ivermectin exposure (68).

Evidence 5b901eaa6d

5-Hydroxy-indol (5-HI) allosterically increases the α7 ACh-induced responses without modifying the response time course or sensitivity to the agonist (69).

Evidence 17545c437d

For example, ivermectin increases the apparent ACh affinity, the slope of the dose-response curve, and the amplitude of nAChR responses (68).

Evidence e56429c50d

Subsequent to the original discovery, several other families suffering from typical ADNFLE or nocturnal frontal lobe epilepsy (NFLE) have been found to have a mutation either in α4 or β2 (encoded by CHRNB2) (165, 166, 168–170).

Evidence 9a53b21f65

Presynaptic and preterminal nicotinic receptors enhance neurotransmitter release, and postsynaptic and nonsynaptic nAChRs mediate excitation as well as activity-dependent modulation of circuits and intracellular enzymatic processes.

Evidence ac456b77fe

Activation of presynaptic nAChRs increases the release of many different neurotransmitters (1, 2, 4, 5, 40, 41, 77–83).

Evidence 0797836767

Presynaptic and preterminal nAChRs increase the release of neurotransmitters in the hippocampus, particularly the main neurotransmitters, GABA and glutamate (41, 78, 81, 97).

Evidence 4d8589b00a

Furthermore, by directly exciting or by shunting the progress of an action potential at a bifurcation, axonal or dendritic nAChRs alter the spread of neuronal excitation.

Evidence 5bb419270d

Nicotinic stimulation enhances glutamate release on multiple timescales, extending from seconds to a few minutes (81), and contributes to the induction of synaptic plasticity (4, 13, 14, 16, 88).

Evidence 7a59f0e649

Decline, disruption, or alterations of nicotinic cholinergic mechanisms have been implicated in various dysfunctions, such as schizophrenia, epilepsy, autism, Alzheimer’s disease (AD), and addiction (17–23).

Evidence b7c155798f

Nicotinic mechanisms contribute to cognitive function, and the decline of nicotinic mechanisms or loss of nAChRs has been observed in AD, dementia with Lewy bodies, Down syndrome, autism, and Parkinson’s disease (20, 140).

Evidence dca06ace4f

Mammalian nAChRs are cation selective, being permeable to small monovalent and divalent cations.

Evidence f8003fef67

Nicotinic receptor activity causes depolarization, and the divalent cation perme- ability plays an important physiological role by supplying ionic signals, including calcium (39–41).

Evidence 78f8f8ebc8

Activation of nAChRs on distal apical dendrites depolarizes the cell and promotes action potential firing

Evidence f1bdfeb187

Nicotinic receptors mediate a small direct calcium influx (42–44, 85).

Evidence 66db0278e0

Furthermore, Src-family kinases (SFKs) directly phosphorylate the cytoplasmic loop of α7 nAChRs in the plasma membrane.

Evidence 1be9d93c47

A mutation in the gene encoding the α4 nAChR subunit (CHRNA4) causes a genetically transmissible form of epilepsy, which was the first discovery of a human disease associated with a neuronal nAChR (165, 166). The mutation has been identified as a single base substitution converting a serine into threonine (S248F) in the TM2 domain of the α4 subunit (165).

Evidence eed996d4b3

Similarly, replacement of the α7 leucine at the synaptic, extracellular end (position 254 or 255) of the pore by threonine dramatically reduced the calcium permeability of the α7 receptors.

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