Desensitization of nicotinic ACh receptors: shaping cholinergic signaling

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Nicotinic ACh receptors (nAChRs) can undergo desensitization, a reversible reduction in response during sustained agonist application. Although the mechanism of desensitization remains incompletely understood, recent investigations have elucidated new properties underlying desensitization, indicating that it might be important to control synaptic efficacy, responses to cholinergic agents, and certain nAChR-related disease states. Thus, studying how different nAChR subunits contribute to desensitization might help to explain variations in responsiveness to drugs, and might thus improve their therapeutic applications. Agonist-specific desensitization, desensitization arising from resting receptors, natural mutations dramatically altering desensitization, and the possibility that recovery from desensitization is an important process for modulating receptor function, together provide a new framework for considering desensitization as a target to shape cholinergic signaling.

Introduction

Nicotinic ACh receptors (nAChRs) are ligand-gated ion channels assembled as pentamers of diverse subunits 1, 2. Usually, nAChRs are fast transducers of signals activated by the transmitter ACh, or by the drug of abuse nicotine 1, 2. Nevertheless, when ACh, nicotine or related agonists are continuously applied, nAChRs become ‘desensitized’ (i.e. temporarily inactive) 3, 4. Desensitization can therefore be seen as a use-dependent, readily reversible form of signal plasticity that might shape synaptic efficacy in various brain regions, or even protect cells from uncontrolled excitation 5, 6, 7, 8. Although the role of nAChR desensitization in normal cholinergic transmission remains unclear, its potential to control cholinergic activity and induce adaptive changes is considerable. In the short period of seconds to minutes, nAChR desensitization underlies the brief skeletal muscle paralysis caused by agents such as succinylcholine during general anesthesia [9]. Over a longer time-frame, nAChR desensitization might be important in understanding the therapeutic efficacy of various nicotinic drugs now used to treat the cholinergic dysfunction associated with neurodegenerative disease 10, 11. Furthermore, nAChR desensitization might even lead to chronic modulation of nAChRs in the brain of tobacco smokers 5, 6, 7. The aim of this review is to clarify the molecular mechanisms involved in nAChR desensitization, the compensatory changes triggered by it, the phenotypes resulting from its alteration, and new strategies for its modulation with the ultimate goal of fine-tuning cholinergic function in health and disease.

Section snippets

Desensitization depends on nAChR subunits

In the mammalian nervous system, nAChRs can be broadly classified as either α7-containing nAChRs that desensitize rapidly (in milliseconds) or non-α7 receptors that desensitize slowly (in seconds) and are made up of various combinations of α and β subunits 1, 2, 4. Among non-α7 receptors, the two most common subtypes are α3β4 (mainly expressed by autonomic neurons and moderately susceptible to desensitization) and α4β2 receptors (widely found in the brain and very prone to desensitization) [4] (

Desensitization kinetic properties

When a medium to high (μM to mM) concentration of agonist is applied, nAChRs are first activated and can then desensitize with subsequent recovery after agonist removal. This process will be referred to here as ‘classical desensitization’ (Figure 1; see Box 1a for kinetic scheme) that develops usually in the range of tens of milliseconds, although different subtypes of nAChRs have differential susceptibility to desensitization (Table 1). Furthermore, nicotine and ACh have differential ability

Agonist-specific recovery from desensitization

In the classical receptor model [3], the recovery from desensitization should be independent of the type of agonist used. Although the recovery from desensitization depends on the nAChR subtype [4], recent findings suggest a novel, agonist-specific rate of recovery for α7 [20], α3β4 [22], α4β2 [16] and muscle-type nAChRs [23]. When the onset and extent of desensitization are similar, the recovery of α4β2 receptors after the removal of nicotine requires much more time than recovery after the

Desensitization and agonist trapping

As originally considered by Katz and Thesleff [3], high affinity of desensitized receptors for agonist indicates that they might be potential traps for unbound agonist molecules 14, 15. Whereas non-α7 receptors possess two agonist-binding sites 24, 25, α7 receptors might theoretically contain up to five binding sites 21, 26, making them especially suited for trapping ACh. At neuromuscular junctions, the ‘trapping’ of released ACh by desensitized receptors can shorten the decay of cholinergic

Molecular determinants of desensitization

The structure of muscle-type nAChRs has been elucidated in electron-microscope studies, under conditions to minimize desensitization (<5 ms agonist application) [25]. Desensitized receptors show a structural transition in which the γ and δ subunits switch to a less-symmetrical configuration [27]. Although identification of the molecular structures underlying desensitization is still incomplete, site-directed mutagenesis within receptor subunits has revealed that replacement of certain elements

Modulation of desensitization

Desensitization is a plastic process, rapidly adapting to changes in neuronal activity through modulation by local factors. One of these is the endogenous peptide substance P, which powerfully facilitates desensitization by binding to an allosteric site distinct from the ACh-recognition sites [41]. Because substance P colocalizes with ACh in the splanchnic nerve terminals in the adrenal gland from which substance P is released in response to stress [41], this peptide might thus attenuate

nAChR desensitization at cholinergic synapses

In the mammalian CNS, excitatory cholinergic transmission mediated by either α7 or non-α7 nAChRs has been observed in GABAergic interneurons of the hippocampus [46], in hypothalamic supraoptic neurons [47], in developing visual cortex neurons [48], in Renshaw cells [49] and in deep interneurons in the spinal cord [50]. Whether the endogenous transmitter ACh can desensitize these receptors has not been systematically investigated. However, hypothalamic nAChRs show modest desensitization, even

nAChR desensitization controls the main action of brain nAChRs to facilitate transmitter release

Although postsynaptic nAChRs can mediate fast cholinergic transmission in the brain, historically nAChRs had been thought to act primarily by controlling the release of other neurotransmitters (e.g. glutamate, GABA and dopamine) from nerve terminals 55, 56, and in this way to regulate synaptic efficacy, synaptic plasticity and cognition, and also nicotine addiction 5, 6. Thus, nAChRs can be viewed as gain-setters of excitatory and inhibitory signals mediated by other transmitters. This effect

Epilepsy and seizures

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a rare form of epilepsy characterized by brief seizures during the night [61]. Several mutations have been found in genes encoding the α4 and β2 neuronal nAChR subunits (although several affected families do not possess any mutations in these genes), many of which reside in or adjacent to M2 of these subunits. Although these mutations produce similar clinical symptoms [62], they have various effects on channel function, including a

Protean actions of nAChRs

The activation and/or regulation of nAChRs, particularly of those containing the α7 subunit, are paradoxically linked to both neuroprotection and neurotoxicity in vivo and in vitro. For example, the neuroprotective action of nicotine in cultured PC12 cells has been suggested to be due to upregulation of α7-containing nAChRs following their persistent desensitization [11]. Such neuroprotection might have clinical implications because some nicotinic ligands appear to minimize the cognitive

Concluding remarks

nAChR desensitization should represent a major target for the upregulation and/or downregulation of nAChR function. By exploiting its dependence on the nAChR subtype, it might be possible in the future to obtain differential regulation of cholinergic signals within the same circuit expressing heterogeneous nAChRs. Furthermore, because desensitization can occur even at agonist concentrations insufficient to activate receptors, it might be possible to minimize drug doses in the interest of safety.

Acknowledgements

This work was supported by PRIN and FIRB grants (to A.N.), by RFFI grants (to R.G.) and by the NIH Intramural program (J.Y.). We would like to thank C. Erxleben and S. Dudek for advice in preparing the manuscript.

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