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The evolutionary origin of the need to sleep: an inevitable consequence of synaptic neurotransmission?

Cantor RS - Front Synaptic Neurosci (2015)

Bottom Line: It is proposed that the evolutionary origin of the need to sleep is the removal of neurotransmitters (NTs) that escape reuptake and accumulate in brain interstitial fluid (ISF).Although NTs are recycled by membrane protein reuptake, the process is less than 100% efficient; a fraction escapes the region in which these specific reuptake proteins are localized and eventually diffuses throughout the ISF.It is estimated that even if only 0.1% of NTs escape reuptake, they would accumulate and adsorb to bilayers in synapses of other receptors sufficiently to affect receptor activity, the harmful consequences of which are avoided by sleep: a period of efficient convective clearance of solutes together with greatly reduced synaptic activity.

View Article: PubMed Central - PubMed

Affiliation: Burke Laboratory, Department of Chemistry, Dartmouth College Hanover, NH, USA ; Memphys Center for Biomembrane Physics, University of Southern Denmark Odense, Denmark.

ABSTRACT
It is proposed that the evolutionary origin of the need to sleep is the removal of neurotransmitters (NTs) that escape reuptake and accumulate in brain interstitial fluid (ISF). Recent work suggests that the activity of ionotropic postsynaptic receptors, rapidly initiated by binding of NTs to extracellular sites, is modulated over longer times by adsorption of these NTs to the lipid bilayers in which the receptors are embedded. This bilayer-mediated mechanism is far less molecularly specific than binding, so bilayer adsorption of NTs that have diffused into synapses for other receptors would modulate their activity as well. Although NTs are recycled by membrane protein reuptake, the process is less than 100% efficient; a fraction escapes the region in which these specific reuptake proteins are localized and eventually diffuses throughout the ISF. It is estimated that even if only 0.1% of NTs escape reuptake, they would accumulate and adsorb to bilayers in synapses of other receptors sufficiently to affect receptor activity, the harmful consequences of which are avoided by sleep: a period of efficient convective clearance of solutes together with greatly reduced synaptic activity.

No MeSH data available.


Related in: MedlinePlus

Effect of a continuously present noncognate NT, at varying concentrations c, on the response of a patch of recombinant receptors to a short (10 ms) pulse of a saturating concentration of their NT agonist, as calculated from the kinetic model with parameter values as detailed in Lee et al. (2015). (A) Representative traces, expressed as the fraction of receptors in the conducting state vs. time, for c = 0 mM (solid line), 0.5 mM (dashed line), 1.2 mM (dotted line), 2.4 mM (dash-dotted line), and 4.0 mM (long dash-dotted line). (B) Total ion flux (i.e., the integrated current) relative to ion flux in the absence of noncognate NT, as a function of c.
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Figure 1: Effect of a continuously present noncognate NT, at varying concentrations c, on the response of a patch of recombinant receptors to a short (10 ms) pulse of a saturating concentration of their NT agonist, as calculated from the kinetic model with parameter values as detailed in Lee et al. (2015). (A) Representative traces, expressed as the fraction of receptors in the conducting state vs. time, for c = 0 mM (solid line), 0.5 mM (dashed line), 1.2 mM (dotted line), 2.4 mM (dash-dotted line), and 4.0 mM (long dash-dotted line). (B) Total ion flux (i.e., the integrated current) relative to ion flux in the absence of noncognate NT, as a function of c.

Mentions: Experimental evidence in support of the second assumption (that bilayer-adsorbed NTs modulate the activity of postsynaptic receptors) was provided by electrophysiological studies (Milutinovic et al., 2007), which clearly showed that the presence of other fast NTs strongly affects the response of receptors to their own NTs. As there are no known binding sites for most noncognate NTs anywhere on the receptors, it supports (although it does not require) a bilayer-mediated mechanism by which NTs nonspecifically influence receptor activity. And as described above, additional support comes from the success of a kinetic model (Cantor et al., 2009; Lee et al., 2015) in predicting the remarkably complex features of electrophysiological traces observed in postsynaptic receptors such as GABAAR, over a broad range of agonist and anesthetic concentrations. Although it incorporates only three protein conformational states (resting, conducting, and desensitized), the model allows for the modulation of the conformational free energy landscape by bilayer adsorption of aqueous solutes, in simple Langmuir approximation. It is capable of reproducing the temporally complex desensitization and deactivation in response to a pulse of agonist, the modulation of those features by volatile anesthetics over a wide range of concentrations (both coapplied with agonist and continuously present), and the activation of receptors by supraclinical anesthetic concentrations in the absence of agonist. In those studies, parameters were determined only for the bilayer-mediated influence of GABA on GABAA receptors, since detailed kinetic data for the effects of noncognate NTs are not available. So, to get a sense for the effect of a different NT on GABAAR, calculations have been performed assuming that the noncognate NT and GABA have similar effects on the bilayer (and thus the same values of the relevant kinetic parameters), but the noncognate NT is unable to bind to the receptor’s activation sites. The results are shown in Figure 1: fo(t), the fraction of receptors in the open (ion-conducting) conformation as a function of time, is predicted in response to a short (10 ms) pulse of a saturating concentration of GABA on a patch of identical GABAA receptors, for varying concentrations (c) of continuously present noncognate NTs. The decrease in the initial peak and the increased rate of deactivation with increasing concentration both contribute to a decrease in the total ion flux Q(c), i.e., the integrated current.


The evolutionary origin of the need to sleep: an inevitable consequence of synaptic neurotransmission?

Cantor RS - Front Synaptic Neurosci (2015)

Effect of a continuously present noncognate NT, at varying concentrations c, on the response of a patch of recombinant receptors to a short (10 ms) pulse of a saturating concentration of their NT agonist, as calculated from the kinetic model with parameter values as detailed in Lee et al. (2015). (A) Representative traces, expressed as the fraction of receptors in the conducting state vs. time, for c = 0 mM (solid line), 0.5 mM (dashed line), 1.2 mM (dotted line), 2.4 mM (dash-dotted line), and 4.0 mM (long dash-dotted line). (B) Total ion flux (i.e., the integrated current) relative to ion flux in the absence of noncognate NT, as a function of c.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4585021&req=5

Figure 1: Effect of a continuously present noncognate NT, at varying concentrations c, on the response of a patch of recombinant receptors to a short (10 ms) pulse of a saturating concentration of their NT agonist, as calculated from the kinetic model with parameter values as detailed in Lee et al. (2015). (A) Representative traces, expressed as the fraction of receptors in the conducting state vs. time, for c = 0 mM (solid line), 0.5 mM (dashed line), 1.2 mM (dotted line), 2.4 mM (dash-dotted line), and 4.0 mM (long dash-dotted line). (B) Total ion flux (i.e., the integrated current) relative to ion flux in the absence of noncognate NT, as a function of c.
Mentions: Experimental evidence in support of the second assumption (that bilayer-adsorbed NTs modulate the activity of postsynaptic receptors) was provided by electrophysiological studies (Milutinovic et al., 2007), which clearly showed that the presence of other fast NTs strongly affects the response of receptors to their own NTs. As there are no known binding sites for most noncognate NTs anywhere on the receptors, it supports (although it does not require) a bilayer-mediated mechanism by which NTs nonspecifically influence receptor activity. And as described above, additional support comes from the success of a kinetic model (Cantor et al., 2009; Lee et al., 2015) in predicting the remarkably complex features of electrophysiological traces observed in postsynaptic receptors such as GABAAR, over a broad range of agonist and anesthetic concentrations. Although it incorporates only three protein conformational states (resting, conducting, and desensitized), the model allows for the modulation of the conformational free energy landscape by bilayer adsorption of aqueous solutes, in simple Langmuir approximation. It is capable of reproducing the temporally complex desensitization and deactivation in response to a pulse of agonist, the modulation of those features by volatile anesthetics over a wide range of concentrations (both coapplied with agonist and continuously present), and the activation of receptors by supraclinical anesthetic concentrations in the absence of agonist. In those studies, parameters were determined only for the bilayer-mediated influence of GABA on GABAA receptors, since detailed kinetic data for the effects of noncognate NTs are not available. So, to get a sense for the effect of a different NT on GABAAR, calculations have been performed assuming that the noncognate NT and GABA have similar effects on the bilayer (and thus the same values of the relevant kinetic parameters), but the noncognate NT is unable to bind to the receptor’s activation sites. The results are shown in Figure 1: fo(t), the fraction of receptors in the open (ion-conducting) conformation as a function of time, is predicted in response to a short (10 ms) pulse of a saturating concentration of GABA on a patch of identical GABAA receptors, for varying concentrations (c) of continuously present noncognate NTs. The decrease in the initial peak and the increased rate of deactivation with increasing concentration both contribute to a decrease in the total ion flux Q(c), i.e., the integrated current.

Bottom Line: It is proposed that the evolutionary origin of the need to sleep is the removal of neurotransmitters (NTs) that escape reuptake and accumulate in brain interstitial fluid (ISF).Although NTs are recycled by membrane protein reuptake, the process is less than 100% efficient; a fraction escapes the region in which these specific reuptake proteins are localized and eventually diffuses throughout the ISF.It is estimated that even if only 0.1% of NTs escape reuptake, they would accumulate and adsorb to bilayers in synapses of other receptors sufficiently to affect receptor activity, the harmful consequences of which are avoided by sleep: a period of efficient convective clearance of solutes together with greatly reduced synaptic activity.

View Article: PubMed Central - PubMed

Affiliation: Burke Laboratory, Department of Chemistry, Dartmouth College Hanover, NH, USA ; Memphys Center for Biomembrane Physics, University of Southern Denmark Odense, Denmark.

ABSTRACT
It is proposed that the evolutionary origin of the need to sleep is the removal of neurotransmitters (NTs) that escape reuptake and accumulate in brain interstitial fluid (ISF). Recent work suggests that the activity of ionotropic postsynaptic receptors, rapidly initiated by binding of NTs to extracellular sites, is modulated over longer times by adsorption of these NTs to the lipid bilayers in which the receptors are embedded. This bilayer-mediated mechanism is far less molecularly specific than binding, so bilayer adsorption of NTs that have diffused into synapses for other receptors would modulate their activity as well. Although NTs are recycled by membrane protein reuptake, the process is less than 100% efficient; a fraction escapes the region in which these specific reuptake proteins are localized and eventually diffuses throughout the ISF. It is estimated that even if only 0.1% of NTs escape reuptake, they would accumulate and adsorb to bilayers in synapses of other receptors sufficiently to affect receptor activity, the harmful consequences of which are avoided by sleep: a period of efficient convective clearance of solutes together with greatly reduced synaptic activity.

No MeSH data available.


Related in: MedlinePlus