Acetylcholine and Acetylcholine Receptors: Textbook Knowledge and New Data

It was a pleasure to receive a proposal to organize and be a guest editor of a Special Issue ofBiomolecules. This is the field in which I am working and personally know some of the leadingscientists. My narrow field is the research on the peptide and protein neurotoxins from animalvenoms and their application as sophisticated tools for analysis of nicotinic acetylcholine receptors(nAChRs) [...].

and of the channel moiety, a very important role was played by Prof. Arthur Karlin (Cornell University, USA) who is a co-author of the above-mentioned paper on the α-bungarotoxin-nAChR complex [3].
Structural analysis results are even more impressive for the muscarinic acetylcholine receptors where 3D structures were determined for all M1-M5 subtypes, and in this issue we have a review by Jakubik and El-Fakahany [4] devoted to one particular problem, namely the allosteric modulation of muscarinic receptors. Interestingly, allosteric modulation is also an important topic for nAChRs and it is appropriate to remind readers that the concept of allosterism for enzymes was introduced first by Monod, Wyman, and Changeux [5] and later was applied most successfully to receptors in the case of nAChRs. The review on muscarinic receptors provided detailed information on the chemical structure of allosteric modulators, on the location of their binding sites, and on their disposition relative to the binding centers for the orthosteric ligands. In combination with the "bitopic" ligands, these compounds are considered as possible routes to drugs against neurological, psychiatric, and neurodegenerative diseases.
All other papers in this issue present experimental results concerning the activity of distinct nAChR subtypes, in order to gain more information on their functioning and to find the ways to new drugs. Much attention is attracted by the α7 nAChRs due to their functional role both in the brain and in the immune system. Working with them is not easy because of problems with their expression and fast desensitization. Deshpande et al. [6] discuss why knock-outs of such chaperons as Ric3 and NACHO differently affect the expression of the α7 nAChRs.
Concerning the role of distinct nAChR subtypes as targets for various drugs, it is appropriate to mention the paper by Qui et al. [7] where it was shown that knock-out of the α10 nAChR subunit in the model of experimental autoimmune encephalomyelitis (EAE) does not grossly change the situation, thus providing further evidence of the disease-exacerbating roles for nAChR containing α9 subunits in EAE inflammatory and autoimmune responses.
In two papers the effects of unusual ligands were tested on different nAChR subtypes. Akimov et al. [8] found that cholines acylated with unsaturated fatty acids (arachidonoyl choline and others), a recently-discovered family of endogenous lipids, behaved as inhibitors of the muscle-type and α7 neuronal nAChR. Lykhmus et al. [9] checked what could be the effects of N-stearoylethanolamine (NSE), a lipid possessing anti-inflammatory, cannabimimetic, and membrane-stabilizing activity, on brain mitochondria sustainability in mice where the α7 nAChRs were knocked-out. This compound stimulated the rise of interleukin-6 in the blood and improved episodic memory of α7-/mice. NSE improved the brain mitochondria sustainability to apoptogenic stimuli and up-regulated α4β2 nAChRs in the brain. It was concluded that the level of alternative nAChR subtypes in the brain is critically important for memory and mitochondria sustainability in the absence of α7 nAChRs.
The role of α7 nAChRs in the cholinergic anti-inflammatory pathway is well known and was earlier shown to affect the expression of several cytokines. Siniavin et al. [10] analyzed it in more detail using α7 nAChR selective agonist PNU 282,987. They confirmed the effects on the expression of such cytokines as IL-6 and IL-10, but for the first time demonstrated the changes in the expression of such membrane molecules as HLA-DR, CD54, CD11b, and CD14 which opens new ways to prevent immunosuppression.

Conflicts of Interest:
The authors declare no conflict of interest.