The impact of receptor desensitization on fast synaptic transmission

Jones, Mathew V.; Westbrook, Gary L.

doi:10.1016/s0166-2236(96)80037-3

Cited by 445 publications

(355 citation statements)

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“…Quantification of the relative and absolute agonist affinities for the desensitized states I and D, with respect to the activatable R state, and the rates that govern the transitions between the various conformations ( Fig. 2) will allow predictions of whether desensitization comes into play following the transient release of a high concentration of neurotransmitter at a synapse (for review see Jones and Westbrook, 1996), or during the prolonged presence of an ambient ligand such as nicotine. Because multiple subtypes of nAChRs, with diverse functional properties, are expressed throughout the nervous system (Role, 1992;Sargent, 1993;Colquhoun and Patrick, 1997;Jones et al, 1999;Cordero-Erausquin et al, 2000), it would seem most useful to consider common features of desensitization for the major types of nAChRs, while highlighting one or two unique characteristics, rather than discussing each receptor in turn.…”

Section: Subunit Contribution To Desensitizationmentioning

confidence: 99%

“…A similar straightforward physiological role for desensitization of ligand-gated ion channels is far from apparent-neurotransmitter is generally not around long enough to provide the continuous stimulation necessary to desensitize these receptors under physiological conditions (Clements, 1996). However, for receptors that desensitize rapidly (e.g., those comprised of ␣7 subunits), or those with high affinities for ACh, which therefore remain bound with agonist for some time after free transmitter is cleared (e.g., ␣4␤2*-nAChRs), desensitization may accumulate during periods of repetitive stimulation, and either lead to loss of response, or if reopening of channels is favorable, would allow prolongation of the synaptic response (Jones and Westbrook, 1996;Paradiso and Brehm, 1998). Alternatively, in the CNS, mismatches between cholinergic terminals and postsynaptic receptors may require ACh to act over a distance (Zoli, 2000), which could lead to desensitization of nAChRs under certain conditions; for example, when acetylcholinesterase is inhibited, endogenous activation of presynaptic nAChRs on dopaminergic terminals in striatum undergoes profound desensitization (Zhou et al, 2001)-a process that may occur during the treatment of Alzheimer's disease using cholinesterase inhibitors.…”

Section: Implications For Desensitization In Physiology and Diseasementioning

confidence: 99%

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Desensitization of neuronal nicotinic receptors

2002

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ABSTRACT:The loss of functional response upon continuous or repeated exposure to agonist, desensitization, is an intriguing phenomenon if not as yet a welldefined physiological mechanism. However, detailed evaluation of the properties of desensitization, especially for the superfamily of ligand-gated ion channels, reveals how the nervous system could make important use of this process that goes far beyond simply curtailing excessive receptor stimulation and the prevention of excitotoxicity. Here we will review the mechanistic basis of desensitization and discuss how the subunit-dependent properties and regulation of nicotinic acetylcholine receptor (nAChR) desensitization contribute to the functional diversity of these channels. These studies provide the essential framework for understanding how the physiological regulation of desensitization could be a major determinant of synaptic efficacy by controlling, in both the short and long term, the number of functional receptors. This type of mechanism can be extended to explain how the continuous occupation of desensitized receptors during chronic nicotine exposure contributes to drug addiction, and highlights the potential significance of prolonged nAChR desensitization that would also occur as a result of extended acetylcholine lifetime during treatment of Alzheimer's disease with cholinesterase inhibitors. Thus, a clearer picture of the importance of nAChR desensitization in both normal information processing and in various diseased states is beginning to emerge.

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Section: Subunit Contribution To Desensitizationmentioning

confidence: 99%

Section: Implications For Desensitization In Physiology and Diseasementioning

confidence: 99%

Desensitization of neuronal nicotinic receptors

2002

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“…A-ring reduced neurosteroids, such as allopregnanolone (3α-hydroxy-5α-pregnan-20-one), THDOC (5α-pregnane-3α,21-diol-20-one) and 3α-diol (5α-androstane-3α,17β-diol) are positive allosteric modulators of the GABA A receptor that augment channel burst durations by increasing the opening frequency (and therefore the relative proportion of long duration single channel events) without concomitant changes in the open duration time constants themselves (for review, Henderson and Jorge, 2004). These positive modulators also slow the rate of recovery from desensitization, thus prolonging deactivation since receptors can transit from high-affinity, bound desensitized states to open states at times after GABA has been cleared from the synaptic cleft (for review, Jones and Westbrook, 1996;Vicini, 2004). At concentrations higher than 100nM, positive neurosteroids can directly gate the GABA A receptor (for review, Belelli et al, 2006), although such actions are unlikely to have physiological effects except, perhaps, during pregnancy when neurosteroids are reported to reach such levels (see Section 4).…”

Section: Mechanisms Of Steroid Modulation Of Gaba a Receptorsmentioning

confidence: 99%

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

Henderson

2007

Neuropharmacology

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The hypothalamus, the seat of neuroendocrine control, is exquisitely sensitive to gonadal steroids. For decades it has been known that androgens, estrogens and progestins, acting through nuclear hormone receptors, elicit both organizational and activational effects in the hypothalamus and basal forebrain that are essential for reproductive function. While changes in gene expression mediated by these classical hormone pathways are paramount in governing both sexual differentiation and the neural control of reproduction, it is also clear that steroids impart critical control of neuroendocrine functions through nongenomic mechanisms. Specifically, endogenous neurosteroid derivatives of deoxycorticosterone, progesterone and testosterone, as well and synthetic anabolic androgenic steroids that are self-administered as drugs of abuse, elicit acute effects via allosteric modulation of γ-aminobutyric acid type A receptors. GABAergic transmission within the hypothalamus and basal forebrain is a key regulator of pubertal onset, the expression of sexual behaviors, pregnancy and parturition. Summarized here are the known actions of steroid modulators on GABAergic transmission within the hypothalamus/basal forebrain, with a focus on the medial preoptic area and the supraoptic/paraventricular nuclei that are known to be central players in the control of reproduction.

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“…The properties of desensitization and recovery from desensitization of the receptors are indeed crucial to shape the physiologic response (Jones and Westbrook, 1996). nAChRs exhibit variable desensitizing behaviors (Lester and Quick, this issue).…”

Section: Physiologic Modes Of Action Of Acetylcholinementioning

confidence: 99%

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

2002

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Nicotinic acetylcholine receptors are made up of homologous subunits, which are encoded by a large multigene family. The wide number of receptor oligomers generated display variable pharmacological properties. One of the main questions underlying research in molecular pharmacology resides in the actual role of this diversity. It is generally assumed that the observed differences between the pharmacology of homologous receptors, for instance, the EC 50 for the endogenous agonist, or the kinetics of desensitization, bear some kind of physiologic relevance in vivo. Here we develop the quite challenging point of view that, at least within a given subfamily of nicotinic receptor subunits, the pharmacologic variability observed in vitro would not be directly relevant to the function of receptor proteins in vivo. In vivo responses are not expected to be sensitive to mild differences in affinities, and several examples of functional replacement of one subunit by another have been unravelled by knockout animals. The diversity of subunits might have been conserved through evolution primarily to account for the topologic diversity of subunit distribution patterns, at the cellular and subcellular levels. A quantitative variation of pharmacological properties would be tolerated within a physiologic envelope, as a consequence of a near-neutral genetic drift. Such a "gratuitous" pharmacologic diversity is nevertheless of practical interest for the design of drugs, which would specifically tackle particular receptor oligomers with a defined subunit composition among the multiple nicotinic receptors present in the organism.

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The impact of receptor desensitization on fast synaptic transmission

Cited by 445 publications

References 81 publications

Desensitization of neuronal nicotinic receptors

Desensitization of neuronal nicotinic receptors

Steroid modulation of GABAA receptor-mediated transmission in the hypothalamus: Effects on reproductive function

The diversity of subunit composition in nAChRs: Evolutionary origins, physiologic and pharmacologic consequences

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