Neuronal Nicotinic Acetylcholine Receptors: From Biophysical Properties to Human Diseases

Abstract

Receptors that mediate neurotransmission can be divided into two groups: the ionotropic and the metabotropic receptors. The ionotropic receptors, which mediate the fast transmission, present both ligand-binding domains and an ion channel and they are usually designed as “ligand-gated channels.” Following the binding of the neurotransmitter molecules, the channel opens and allows ions to flow across the membrane, which then displace the cell potential toward the electrochemical equilibrium of the permeable ions. Differently, metabotropic receptors display a binding site for the ligand that triggers protein-protein interactions or catalytic activities leading to the activation of second messenger pathways. Among the ligand-gated channels three main families are distinguished: the family of glutamate receptors (kainate/a-amino- 3-hydroxy-5-methyl-4-isoxazoleprionic acid, AMPA, and _N-methyl-D- aspartate, NMDA), the family of the purinergic receptors, and the family of the nicotinic acetylcholine receptors (nAChRs). This last family includes the 7-aminobutyric acid (GABA)-A receptors, the glycine receptors, the serotoninergic 5-hydroxytryptophan (5-HT₃) receptors, and the nAChRs (ORTELLS and LUNT 1995). Whilst the GABA and glycine receptors are selectively permeable to anions, the nAChRs and 5-HT₃ receptors are selective for cations. The analysis of DNA sequences supports the notion that the nAChRs share a common evolutionary ancestor, probably homomeric, with the GABA_A, the glycine, and the 5-HT₃ receptors (LE NOVERE and CHANGEUX 1995; ORTELLS and LUNT 1995). According to this scheme it is supposed that throughout evolution, gene duplication and spontaneous mutations have progressively led to the emergence of the different receptor subtypes. All of the receptors that belong to this family result from the assembly of five subunits, each of which is a single protein with four transmembrane domains (BERTRAND and CHANGEUX 1995; GALZI and CHANGEUX 1995). To date, 11 neuronal nAChR subunits have been identified in the vertebrates: eight genes code for a subunits (a2-cc9) and three for non-a subunits identified as α2–α4 (LINDSTROM 1997; MCGEHEE and ROLE 1995). As described above, it is well accepted that the most ancient forms of nAChRs are the homo-oligomeric receptors: al-a9 (LE NOVERE and CHANGEUX 1995; ORTELLS and LUNT 1995). Predictions made from the DNA sequences suggest that the muscle receptor is a specialized and recent type of nAChR. The last bifurcation is supposed to have taken place shortly before the onset of the mammalian lineage (420 million years ago), paralleling the progressive increased complexity of the chordate nervous system, in particular the cholinergic systems (LE NOVERE and CHANGEUX 1995).