Characterization of the human nicotinic acetylcholine receptor subunit alpha (α) 9 (CHRNA9) and alpha (α) 10 (CHRNA10) in lymphocytes

Peng, Hong; Ferris, Robert L.; Matthews, Tonya; Hiel, Hakim; López-Albaitero, Andrés; Lustig, Lawrence R.

doi:10.1016/j.lfs.2004.05.031

Cited by 126 publications

(117 citation statements)

References 39 publications

(55 reference statements)

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“…These findings led to the conclusion that the ATP-mediated signaling is inhibited by nicotinic receptors and that inflammasome assembly triggered by ATP-independent stimuli is unimpaired. However, nicotine alone did not induce ion currents, indicating that nicotinic ACh receptors expressed by U937 cells do not form functional ion channels as was described previously for monocytes and other leukocytes (11,32,33). At such unconventional metabotropic nicotinic ACh receptors, antagonists of canonical ionotropic receptors can gain agonist activity (33), which is in line with the present observation that nicotine shares activity with ACh and choline in inhibiting BzATP-induced IL-1b release while acting as an antagonist of ionotropic CHRNA9/CHRNA10 (22).…”

Section: Discussionsupporting

confidence: 56%

Phosphocholine-Modified Macromolecules and Canonical Nicotinic Agonists Inhibit ATP-Induced IL-1β Release

Hecker

Küllmar

Wilker

et al. 2015

The Journal of Immunology

199

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IL-1β is a potent proinflammatory cytokine of the innate immune system that is involved in host defense against infection. However, increased production of IL-1β plays a pathogenic role in various inflammatory diseases, such as rheumatoid arthritis, gout, sepsis, stroke, and transplant rejection. To prevent detrimental collateral damage, IL-1β release is tightly controlled and typically requires two consecutive danger signals. LPS from Gram-negative bacteria is a prototypical first signal inducing pro–IL-1β synthesis, whereas extracellular ATP is a typical second signal sensed by the ATP receptor P2X7 that triggers activation of the NLRP3-containing inflammasome, proteolytic cleavage of pro–IL-1β by caspase-1, and release of mature IL-1β. Mechanisms controlling IL-1β release, even in the presence of both danger signals, are needed to protect from collateral damage and are of therapeutic interest. In this article, we show that acetylcholine, choline, phosphocholine, phosphocholine-modified LPS from Haemophilus influenzae, and phosphocholine-modified protein efficiently inhibit ATP-mediated IL-1β release in human and rat monocytes via nicotinic acetylcholine receptors containing subunits α7, α9, and/or α10. Of note, we identify receptors for phosphocholine-modified macromolecules that are synthesized by microbes and eukaryotic parasites and are well-known modulators of the immune system. Our data suggest that an endogenous anti-inflammatory cholinergic control mechanism effectively controls ATP-mediated release of IL-1β and that the same mechanism is used by symbionts and misused by parasites to evade innate immune responses of the host.

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Section: Discussionsupporting

confidence: 56%

Phosphocholine-Modified Macromolecules and Canonical Nicotinic Agonists Inhibit ATP-Induced IL-1β Release

Hecker

Küllmar

Wilker

et al. 2015

The Journal of Immunology

199

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“…The mechanism by which nicotine increases [Ca 2ϩ ] i in non-neuronal cells is unclear. Based mostly on PCR analysis, T cells have been reported to express a number of different nAChR subunits (25,29), but their role in the nicotine-induced Ca 2ϩ influx has not been clearly established. Indeed, in T cells, there is no published electrophysiological evidence to support the presence of ligand-gated cation channels responsive to nicotine.…”

Section: Discussionmentioning

confidence: 99%

“…In vivo, nicotine regulates T cell function by direct interaction with T cells and indirectly through neuroimmune interactions (18,24). RT-PCR analysis suggests the expression of ␣7-like nAChR nucleotide sequences in T cells (25)(26)(27)(28)(29), but their structure and function have not been clearly identified. Exposure of T cells to nicotine stimulates protein tyrosine kinase (PTK) activities and raises the [Ca 2ϩ ] i concentration (18), indicating that T cells respond directly to nicotine.…”

Section: T He Nicotinic Acetylcholine Receptors (Nachrs)mentioning

confidence: 99%

T Cells Express α7-Nicotinic Acetylcholine Receptor Subunits That Require a Functional TCR and Leukocyte-Specific Protein Tyrosine Kinase for Nicotine-Induced Ca2+ Response

Razani‐Boroujerdi

Boyd

Dávila‐García

et al. 2007

The Journal of Immunology

153

131

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Acute and chronic effects of nicotine on the immune system are usually opposite; acute treatment stimulates while chronic nicotine suppresses immune and inflammatory responses. Nicotine acutely raises intracellular calcium ([Ca2+]i) in T cells, but the mechanism of this response is unclear. Nicotinic acetylcholine receptors (nAChRs) are present on neuronal and non-neuronal cells, but while in neurons, nAChRs are cation channels that participate in neurotransmission; their structure and function in nonexcitable cells are not well-defined. In this communication, we present evidence that T cells express α7-nAChRs that are critical in increasing [Ca2+]i in response to nicotine. Cloning and sequencing of the receptor from human T cells showed a full-length transcript essentially identical to the neuronal α7-nAChR subunit (>99.6% homology). These receptors are up-regulated and tyrosine phosphorylated by treatment with nicotine, anti-TCR Abs, or Con A. Furthermore, knockdown of the α7-nAChR subunit mRNA by RNA interference reduced the nicotine-induced Ca2+ response, but unlike the neuronal receptor, α-bungarotoxin and methyllycaconitine not only failed to block, but also actually raised [Ca2+]i in T cells. The nicotine-induced release of Ca2+ from intracellular stores in T cells did not require extracellular Ca2+, but, similar to the TCR-mediated Ca2+ response, required activation of protein tyrosine kinases, a functional TCR/CD3 complex, and leukocyte-specific tyrosine kinase. Moreover, CD3ζ and α7-nAChR coimmunoprecipitated with anti-CD3ζ or anti-α7-nAChR Abs. These results suggest that in T cells, α7-nAChR, despite its close sequence homology with neuronal α7-nAChR, fails to form a ligand-gated Ca2+ channel, and that the nicotine-induced rise in [Ca2+]i in T cells requires functional TCR/CD3 and leukocyte-specific tyrosine kinase.

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“…These nAChRs are also expressed in other diverse tissue locations such as the dorsal root ganglia (Ellison et al, 2006;Lips et al, 2002), lymphocytes (Lustig et al, 2001;Peng et al, 2004), and sperm (Kumar and Meizel, 2005). Since these receptors have been difficult to study in mammalian heterologous expression systems, very little is known about the accessory molecules that regulate the function of these neuronal nAChRs.…”

Section: Discussionmentioning

confidence: 99%

Muscle-like nicotinic receptor accessory molecules in sensory hair cells of the inner ear

Osman

Schrader

Hawkes

et al. 2008

Molecular and Cellular Neuroscience

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Nothing is known about the regulation of nicotinic acetylcholine receptors (nAChRs) in hair cells of the inner ear. MuSK, rapsyn and RIC-3 are accessory molecules associated with muscle and brain nAChR function. We demonstrate that these accessory molecules are expressed in the inner ear raising the possibility of a muscle-like mechanism for clustering and assembly of nAChRs in hair cells. We focused our investigations on rapsyn and RIC-3. Rapsyn interacts with the cytoplasmic loop of nAChR α9 subunits but not nAChR α10 subunits. Although rapsyn and RIC-3 increase nAChR α9 expression, rapsyn plays a greater role in receptor clustering while RIC-3 is important for acetylcholine-induced calcium responses. Our data suggest that RIC-3 facilitates receptor function, while rapsyn enhances receptor clustering at the cell surface.

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Characterization of the human nicotinic acetylcholine receptor subunit alpha (α) 9 (CHRNA9) and alpha (α) 10 (CHRNA10) in lymphocytes

Cited by 126 publications

References 39 publications

Phosphocholine-Modified Macromolecules and Canonical Nicotinic Agonists Inhibit ATP-Induced IL-1β Release

Phosphocholine-Modified Macromolecules and Canonical Nicotinic Agonists Inhibit ATP-Induced IL-1β Release

T Cells Express α7-Nicotinic Acetylcholine Receptor Subunits That Require a Functional TCR and Leukocyte-Specific Protein Tyrosine Kinase for Nicotine-Induced Ca2+ Response

Muscle-like nicotinic receptor accessory molecules in sensory hair cells of the inner ear

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