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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We are very grateful for Dr. Roger Papke’s key suggestion of employing the positive allosteric modulator PNU-120596 in our cell-attached patch clamp experiments. This project was supported by the National Center for Research Resources (NCRR) grant U54RR026139, the National Institute on Minority Health and Health Disparities (NIMHD) grant 8U54MD007587-03, the National Institute of Neurological Disorders and Stroke (NINDS) grant U54NS0430311, the National Institute of General Medical Sciences (NIGMS) grant 1P20GM103642, and the National Institute of Mental Health (NIMH) grant P30MH075673-07. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health (NIH). Manuel Delgado-Vélez was supported by the University of Puerto Rico, Río Piedras Campus, Research Initiative for Scientific Enhancement (RISE) Program grant 2R25GM061151-5A1.
Conflict of Interest
The authors declare that they have no conflict of interest.
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