Editorial: To channel or not to channel? Functioning of nicotinic acetylcholine receptors in leukocytes

Skok, Maryna

doi:10.1189/jlb.0209106

Cited by 39 publications

(38 citation statements)

References 11 publications

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“…It has been previously reported that ACh does not elicit macroscopic currents in immune cells that express the α7 nicotinic receptor (Villiger et al 2002; Skok 2009), an observation that we too have made (data not shown). Nonetheless, our results demonstrate that the macrophage α7 retains its ion translocation functionality as judged by single-channel recordings performed on human MDMs.…”

Section: Resultssupporting

confidence: 68%

“…Therefore, activation of this nicotinic receptor can initiate calcium-dependent signaling cascades (Shen and Yakel 2009). While the ion translocation activity of the α7 has been extensively studied by various electrophysiological techniques, whole-cell patch clamp studies performed in peripheral blood mononuclear cells (Villiger et al 2002; Skok 2009) have failed to demonstrate α7 macroscopic currents in these cells. While previous studies have reported the essential role of the α7 in the regulation of inflammation (Wang et al 2003) none have shown, to the best of our knowledge, evidence of α7 ion translocation activity in macrophages.…”

Section: Introductionmentioning

confidence: 99%

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Activation of the Macrophage α7 Nicotinic Acetylcholine Receptor and Control of Inflammation

Baéz-Pagán

Delgado-Vélez

Lasalde‐Dominicci

2015

J Neuroimmune Pharmacol

161

130

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Inflammatory responses to stimuli are essential body defenses against foreign threats. However, uncontrolled inflammation may result in serious health problems, which can be life-threatening. The α7 nicotinic acetylcholine receptor, a ligand-gated ion channel expressed in the nervous and immune systems, has an essential role in the control of inflammation. Activation of the macrophage α7 receptor by acetylcholine, nicotine, or other agonists, selectively inhibits production of pro-inflammatory cytokines while leaving anti-inflammatory cytokines undisturbed. The neural control of this regulation pathway was discovered recently and it was named the cholinergic anti-inflammatory pathway (CAP). When afferent vagus nerve terminals are activated by cytokines or other pro-inflammatory stimuli, the message travels through the afferent vagus nerve, resulting in action potentials traveling down efferent vagus nerve fibers in a process that eventually leads to macrophage α7 activation by acetylcholine and inhibition of pro-inflammatory cytokines production. The mechanism by which activation of α7 in macrophages regulates pro-inflammatory responses is subject of intense research, and important insights have thus been made. The results suggest that activation of the macrophage α7 controls inflammation by inhibiting NF-κB nuclear translocation, and activating the JAK2/STAT3 pathway among other suggested pathways. While the α7 is well characterized as a ligand-gated ion channel in neurons, whole-cell patch clamp experiments suggest that α7’s ion channel activity, defined as the translocation of ions across the membrane in response to ligands, is absent in leukocytes, and therefore, ion channel activity is generally assumed not to be required for the operation of the CAP. In this perspective, we briefly review macrophage α7 activation as it relates to the control of inflammation, and broaden the current view by providing single-channel currents as evidence that the α7 expressed in macrophages retains its ion translocation activity despite the absence of whole-cell currents. Whether this ion-translocating activity is relevant for the proper operation of the CAP or other important physiological processes remains obscure.

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Section: Resultssupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Activation of the Macrophage α7 Nicotinic Acetylcholine Receptor and Control of Inflammation

Baéz-Pagán

Delgado-Vélez

Lasalde‐Dominicci

2015

J Neuroimmune Pharmacol

161

130

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“…The a 7 -type homomeric nAChR has an especially interesting array of conducting and nonconducting conformational states, regulated by both orthosteric and allosteric ligands (Williams et al, 2011a). It was recently proposed that the a 7 receptor may mediate both channel activation-dependent and -independent forms of signaling (de Jonge and Ulloa, 2007;Skok, 2009;Kabbani et al, 2013). Therefore, understanding the pharmacophore for selectively inducing specific nonconducting states may be of equal interest and importance as understanding the pharmacophore for inducing open channel states.…”

Section: Introductionmentioning

confidence: 99%

The Minimal Pharmacophore for Silent Agonism of the α₇ Nicotinic Acetylcholine Receptor

Papke

Chojnacka

Horenstein

2014

J Pharmacol Exp Ther

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The minimum pharmacophore for activation of the human a 7 nicotinic acetylcholine receptor (nAChR) is the tetramethylammonium cation. Previous work demonstrated that larger quaternary ammonium compounds, such as diethyldimethylammonium or 1-methyl quinuclidine, were a 7 -selective partial agonists, but additional increase in the size of the ammonium cation or the quinuclidine N-alkyl group by a single carbon to an N-ethyl group led to a loss of efficacy for ion channel activation. We report that although such compounds are ineffective at inducing the normal channel open state, they nonetheless regulate the induction of specific conformational states normally considered downstream of channel activation. We synthesized several panels of quaternary ammonium nAChR ligands that systematically varied the size of the substituents bonded to the central positively charged nitrogen atom. In these molecular series, we found a correlation between the molecular volume of the ligand and/or charge density, and the receptor's preferred distribution among conformational states including the closed state, the active state, a nonconducting state that could be converted to an activated state by a positive allosteric modulator (PAM), and a PAM-insensitive nonconducting state. We hypothesize that the changes of molecular volume of an agonist's cationic core subtly impact interactions at the subunit interface constituting the orthosteric binding site in such a way as to regulate the probability of conversions among the conformational states. We define a new minimal pharmacophore for the class of compounds we have termed "silent agonists," which are able to induce allosteric modulator-dependent activation but not the normal activated state.

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“…Identification of compounds that preferentially stabilize specific functional states, including D s and D i , may be therapeutically important if it can be shown that a specific state is important for signal transduction attributed to ␣7. It is noteworthy that ␣7-mediated signal transduction has been observed under conditions in which ion channel activation is not apparent (Skok, 2009), leaving open the intriguing possibility that ␣7-desensitized states are not inactive but functionally meaningful.…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Molecular Mechanism of the α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulator PNU-120596 Provides Evidence for Two Distinct Desensitized States

Williams

Wang²,

Papke³

2011

Molecular Pharmacology

101

210

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Although ␣7 nicotinic acetylcholine receptors are considered potentially important therapeutic targets, the development of selective agonists has been stymied by the ␣7 receptor's intrinsically low probability of opening (P open ) and the concern that an agonist-based therapeutic approach would disrupt endogenous cholinergic function. Development of ␣7 positive allosteric modulators (PAMs) holds promise of avoiding both issues. N-(5-Chloro-2,4-dimethoxyphenyl)-NЈ-(5-methyl-3-isoxazolyl)-urea (PNU-120596) is one of the most effective ␣7 PAMs, with a mechanism associated, at least in part, with the destabilization of desensitized states. We studied the mechanism of PNU-120596 potentiation of ␣7 receptors expressed in Xenopus laevis oocytes and outside-out patches from BOSC 23 cells. We identify two forms of ␣7 desensitization: one is destabilized by PNU-120596 (D s ), and the other is induced by strong episodes of activation and is stable in the presence of the PAM (D i ). Our characterization of prolonged bursts of single-channel currents that occur with PNU-120596 provide a remarkable contrast to the behavior of the channels in the absence of the PAM. Individual channels that avoid the D i state show a 100,000-fold increase in P open compared with receptors in the nonpotentiated state. In the presence of PNU-120596, balance between D s and D i is dynamically regulated by both agonist and PAM binding, with maximal ion channel activity at intermediate levels of binding to both classes of sites. In the presence of high agonist concentrations, competitive antagonists may have the effect of shifting the balance in favor of D s and increasing ion channel currents.

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Editorial: To channel or not to channel? Functioning of nicotinic acetylcholine receptors in leukocytes

Cited by 39 publications

References 11 publications

Activation of the Macrophage α7 Nicotinic Acetylcholine Receptor and Control of Inflammation

Activation of the Macrophage α7 Nicotinic Acetylcholine Receptor and Control of Inflammation

The Minimal Pharmacophore for Silent Agonism of the α₇ Nicotinic Acetylcholine Receptor

Investigation of the Molecular Mechanism of the α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulator PNU-120596 Provides Evidence for Two Distinct Desensitized States

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Editorial: To channel or not to channel? Functioning of nicotinic acetylcholine receptors in leukocytes

Cited by 39 publications

References 11 publications

Activation of the Macrophage α7 Nicotinic Acetylcholine Receptor and Control of Inflammation

Activation of the Macrophage α7 Nicotinic Acetylcholine Receptor and Control of Inflammation

The Minimal Pharmacophore for Silent Agonism of the α7 Nicotinic Acetylcholine Receptor

Investigation of the Molecular Mechanism of the α7 Nicotinic Acetylcholine Receptor Positive Allosteric Modulator PNU-120596 Provides Evidence for Two Distinct Desensitized States

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The Minimal Pharmacophore for Silent Agonism of the α₇ Nicotinic Acetylcholine Receptor