α7- and α9-Containing Nicotinic Acetylcholine Receptors in the Functioning of Immune System and in Pain

Abstract

Nicotinic acetylcholine receptors (nAChRs) present as many different subtypes in the nervous and immune systems, muscles and on the cells of other organs. In the immune system, inflammation is regulated via the vagus nerve through the activation of the non-neuronal α7 nAChR subtype, affecting the production of cytokines. The analgesic properties of α7 nAChR-selective compounds are mostly based on the activation of the cholinergic anti-inflammatory pathway. The molecular mechanism of neuropathic pain relief mediated by the inhibition of α9-containing nAChRs is not fully understood yet, but the role of immune factors in this process is becoming evident. To obtain appropriate drugs, a search of selective agonists, antagonists and modulators of α7- and α9-containing nAChRs is underway. The naturally occurring three-finger snake α-neurotoxins and mammalian Ly6/uPAR proteins, as well as neurotoxic peptides α-conotoxins, are not only sophisticated tools in research on nAChRs but are also considered as potential medicines. In particular, the inhibition of the α9-containing nAChRs by α-conotoxins may be a pathway to alleviate neuropathic pain. nAChRs are involved in the inflammation processes during AIDS and other viral infections; thus they can also be means used in drug design. In this review, we discuss the role of α7- and α9-containing nAChRs in the immune processes and in pain.

Keywords: Ly6/uPAR proteins; Lynx1; SLURP-1; anti-inflammatory pathway; chronic pain; nicotinic acetylcholine receptors; viral infection; α-conotoxins.

Figure 1

The ribbon presentation of spatial structures of three-fingered toxins as well as different complexes of the target ligand from NMR, X-ray or cryo-EM studies. (A) From left to right: X-ray structures of long-chain α-cobratoxin from Naja kaouthia (PDB ID: 2CTX) and short-chain erabutoxin-a from Laticauda semifasciata (PDB ID: 5EBX) as well as NMR structures of non-conventional candoxin from Bungarus candidus (PDB ID: 1JGK) and human water-soluble Lynx1 protein (PDB ID: 2L03). Four “core” disulfides are shown in yellow and the fifth disulfide, if any, are in blue. Three loops are indicated in all cases. (B) Top and side view of the cryo-EM structure of pentameric construct based on human α7 nAChR complexed with α-bungarotoxin (PDB ID: 7KOO). Identical subunits of the receptor are shown with different colors of green for clarity, and five toxins are in red. (C) Top and side view of the X-ray structure of pentameric chimera based on human α7 nAChR extracellular domain (ECD) and Lymnaea stagnalis AChBP complexed with α-bungarotoxin (PDB ID: 4HQP). Identical protomers are shown with different colors of green for clarity, and five toxins are in red. (D) Top and side view of the X-ray structure of Aplysia californica AChBP complexed with α-conotoxin PnIA analogue (PDB ID: 2BR8). Identical protein protomers are shown with different colors of blue for clarity, and five conotoxins are in red. (E) Top and side view of the X-ray structure of monomer of human α9 nAChR ECD (in blue) complexed with α-conotoxin RgIA (in red) (PDB ID: 6HY7).