Merging old and new perspectives on nicotinic acetylcholine receptors

Abstract

This review covers history underlying the discovery of the molecular mediators of nicotine's effects in the brain and the diversity of the nicotinic acetylcholine receptor (nAChR) subtypes. Models are presented for both their structure and their function as mediators of signal transduction, with special consideration of the differences between the two main subtypes: heteromeric receptors, which are specialized for rapid electrochemical signal transduction, and homomeric α7 receptors, which have come to be implicated in both ionotropic and metabotropic signaling. This review presents perspectives on the pharmacology and therapeutic targeting of nAChRs for the treatment of nicotine dependence or disease.

Keywords: Allosteric proteins; Electrophysiology; Molecular biology; Signal transduction; Synaptic function.

Figure 1

Structural elements of nAChR subunits and analogs represented with hydrophobicity profiles. The Kyte-Doolittle plots were generated in DNA Strider (CEA, France). A) Human α1 subunit. B) Bacterial homolog of Cys-loop ligand-gated ion channels, GLIC. Note the absence of any intracellular domain. C) The snail AChBP which has been used for homology modeling of nAChRs. D) The fingerprinting of human nAChR alpha subunits based on their diverse intracellular domains. E) The alignment of α7 intracellular domains from different species. The numbers on the X-axis are based on the amino acid sequence of the α1 subunit in panel A and the respective alignments in the other panels.

Figure 2

Homology model [106] of the interface between α4 and β2 subunits highlighting the subdomains important for agonist binding that are located on the primary (Loops A, B, and C in the α4 subunit) or complementary surface (Loops D, E, and F in the β2 subunit) of the ligand binding domain. Only the contours of the backbone are shown except for the disulfide-linked vicinal cysteines on the C-loop of α4. The figure was prepared in UCSF Chimera by Dr. Nicole Horenstein.

Figure 3

Models for the activation and desensitization of heteromeric nAChRs. A) Cartoons of the conformational states of nAChRs highlighting the transmembrane topology and key elements associated with ligand binding and conformational change. B) Theoretical energy landscapes for heteromeric nAChRs with different levels of agonist occupancy. C) Time-dependent changes in the occupation of conformational states by a population of receptors following an instantaneous jump in agonist concentration. The diameter of the red circle represents the proportion of channels in each state at different times.

Figure 4

A) Hypothetical energy landscapes for the activation of α4β2 nAChRs by either ACh (Figure 3) or nicotine. Note that nicotine more effectively stabilizes the desensitized state than does ACh. B) Hypothetical time-dependent changes in the occupation of conformational states by a population of receptors following an instantaneous jump in nicotine concentration. Note that although there is initially less synchronous activation of channels than predicted for ACh (see Figure 3C), there is more steady-state current after equilibration is achieved.