Nicotinic ACh receptors as therapeutic targets in CNS disorders

Abstract

The neurotransmitter acetylcholine (ACh) can regulate neuronal excitability by acting on the cys-loop cation-conducting ligand-gated nicotinic ACh receptor (nAChR) channels. These receptors are widely distributed throughout the central nervous system (CNS), being expressed on neurons and non-neuronal cells, where they participate in a variety of physiological responses such as anxiety, the central processing of pain, food intake, nicotine seeking behavior, and cognitive functions. In the mammalian brain, nine different subunits have been found thus far, which assemble into pentameric complexes with much subunit diversity; however, the α7 and α4β2 subtypes predominate in the CNS. Neuronal nAChR dysfunction is involved in the pathophysiology of many neurological disorders. Here we will briefly discuss the functional makeup and expression of the nAChRs in mammalian brain, and their role as targets in neurodegenerative diseases (in particular Alzheimer's disease, AD), neurodevelopmental disorders (in particular autism and schizophrenia), and neuropathic pain.

Keywords: cys-loop receptor; nAChR; α4β2 receptor; α7 receptor.

Figure 1. Nicotinic ACh receptor channel; basic structure and functional properties

Molecular model of the rat α7 nAChR with ligand-binding from a side view showing the ligand-binding, transmembrane, and intracellular domain (A), and a top down view (B) showing the pentameric nature of the receptor with the ligand-binding pocket at the interface between two subunits. C, The basic functional and pharmacological properties of the α7 and α4β2 nAChR subtypes.

Figure 2

A, Aβ is formed through proteolytic cleavage of its precursor protein, a type 1 membrane protein called amyloid precursor protein (APP). APP cleavage by β- and γ-secretases lead to the formation of the N- and C-terminal residues of Aβ, respectively, in addition to soluble APP (sAPPβ) and a C-terminal fragment (CTF) of 99 amino acids (C99). If APP is cleaved by the α-secretase, then Aβ formation is precluded as this enzyme cleaves APP within the Aβ sequence to generate sAPPα and CTF83. When cleaved by γ-secretase, CTFs generate the AICD (APP intracellular domain) and either P3 or Aβ resulting from α- and β-secretase cleavage, respectively. B, As Aβ accumulates one can postulate that at lower concentration and smaller oligomer aggregates (upper panel), transient nAChR activation may occur depending on the nAChR subunit composition (Table 2). If activation ensues, it can lead to membrane depolarization, increased intracellular/presynaptic calcium and synaptic transmission, activation of kinases important for synaptic plasticity, learning and memory as well as the induction of genes and proteins necessary for the cholinergic phenotype and neuroprotection. As disease progresses and Aβ concentration and oligomer status increase (lower panel), nAChR function is lost either through loss of receptor protein (α4β2^*) or function (α7^*) leading to synaptic dysfunction and loss of the cholinergic phenotype, learning and memory deficits, increased inflammatory status and progressive neurodegeneration.