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Understanding structure–function relationships of the human neuronal acetylcholine receptor: insights from the first crystal structures of neuronal subunits
Author(s) -
Giastas Petros,
Zouridakis Marios,
Tzartos Socrates J
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13838
Subject(s) - nicotinic agonist , neuroscience , cys loop receptors , acetylcholine receptor , ligand gated ion channel , acetylcholine , epibatidine , neurotransmitter receptor , ion channel , receptor , glycine receptor , nicotinic acetylcholine receptor , ligand (biochemistry) , neurotransmitter , biology , chemistry , biochemistry , central nervous system , pharmacology , amino acid , glycine
Nicotinic ACh receptors (nAChRs) are the best studied members of the superfamily of pentameric ligand-gated ion channels (pLGICs). Neuronal nAChRs regulate neuronal excitability and neurotransmitter release in the nervous system and form either homo- or hetero-pentameric complexes with various combinations of the 11 neuronal nAChR subunits (α2-7, α9, α10 and β2-4) known to exist in humans. In addition to their wide distribution in the nervous system, neuronal nAChRs have been also found in immune cells and many peripheral tissues. These nAChRs are important drug targets for neurological and neuropsychiatric diseases (e.g. Alzheimer's, schizophrenia) and substance addiction (e.g. nicotine), as well as in a variety of diseases such as chronic pain, auditory disorders and some cancers. To decipher the functional mechanisms of human nAChRs and develop efficient and specific therapeutic drugs, elucidation of their high-resolution structures is needed. Recent studies, including the X-ray crystal structures of the near-intact α4β2 nAChR and of the ligand-binding domains of the α9 and α2 subunits, have advanced our knowledge on the detailed structure of the ligand-binding sites formed between the same and different subunits and revealed many other functionally important interactions. The aim of this review is to highlight some of the structural and functional findings of these studies and to compare them with recent breakthrough findings on other pLGIC members and earlier data from their homologous ACh-binding proteins.