Ivermectin is an example of a positive allosteric effector that modifies the pharmacological profile of the α7 nAChR.
Activation and desensitization of nAChRs by bath-applied nicotine also increases LTD induced by a stimulus train
The nicotine initially activates nAChRs on DA neurons, causing an increase in burst firing and overall firing rate (88, 121, 123, 124, 134).
Results show that genistein does not alter the surface expression of nAChRs, but rather it modifies nAChRs in the cell membrane (71).
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).
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).
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).
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).
This calcium influx can trigger calcium-induced calcium release from intracellular stores (86).
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).
The combination of enhanced glutamatergic release and strong postsynaptic response produces LTP of the glutamatergic afferents.
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.
In general, nicotinic agonists improve certain forms of memory, and nicotinic antagonists and cholinergic lesions impair memory (5, 141–145).
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).
During attention tasks, the nicotinic antagonist, mecamylamine, impaired accuracy or reaction time (151, 152) and nicotinic agonists improved accuracy (153).
Consistent with these treatments, nicotinic agents improve cognitive deficits of AD patients (20, 158).
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.
The α7 nAChR has a relatively low affinity for ACh activation, with an effective dose for half-activation at approximately 200 μM ACh.
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).
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).
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).
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).
Simultaneously, nicotine activates presynaptic α7∗ nAChRs, boosting glutamatergic synaptic transmission onto DA neurons (23, 88, 123, 134).
Moreover, although nicotine increases wakefulness in wild-type mice, it does not affect β2−/− mice. Overall, stimulation of nAChRs promotes arousal and REM sleep.
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.
Postsynaptic β2∗ nAChRs initially depolarize DA neurons, causing them to fire action potentials while presynaptic α7∗ nAChRs boost glutamate release.
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).
In addition, nAChR activity produces a depolarization that activates voltage-gated calcium channels in the presynaptic terminal (87).
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).
As AD worsens, cholinergic neurons are progressively lost and the number of nAChRs declines, particularly in the hippocampus and cortex (140, 158).
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).
Nicotinic receptors also modulate glutamatergic synaptic plasticity.
Genetic evidence has linked nicotinic receptors to epilepsy and schizophrenia, and studies with mutant mice have implicated nAChRs in pain mechanisms, anxiety, and depression.
Cholinergic volume transmission enables ACh to diffuse and to act at lower concentrations some distance away from the release site.
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.
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.
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).
Dimethylphenylpiperazidium (DMPP) normally is a partial agonist at this receptor subtype, but it becomes almost a full agonist following ivermectin exposure (68).
5-Hydroxy-indol (5-HI) allosterically increases the α7 ACh-induced responses without modifying the response time course or sensitivity to the agonist (69).
For example, ivermectin increases the apparent ACh affinity, the slope of the dose-response curve, and the amplitude of nAChR responses (68).
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).
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.
Activation of presynaptic nAChRs increases the release of many different neurotransmitters (1, 2, 4, 5, 40, 41, 77–83).
Presynaptic and preterminal nAChRs increase the release of neurotransmitters in the hippocampus, particularly the main neurotransmitters, GABA and glutamate (41, 78, 81, 97).
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.
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).
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).
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).
Mammalian nAChRs are cation selective, being permeable to small monovalent and divalent cations.
Nicotinic receptor activity causes depolarization, and the divalent cation perme- ability plays an important physiological role by supplying ionic signals, including calcium (39–41).
Activation of nAChRs on distal apical dendrites depolarizes the cell and promotes action potential firing
Nicotinic receptors mediate a small direct calcium influx (42–44, 85).
Furthermore, Src-family kinases (SFKs) directly phosphorylate the cytoplasmic loop of α7 nAChRs in the plasma membrane.
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).
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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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.