Nicotinic acetylcholine receptors: key targets for attenuating neurodegenerative diseases

Organisms have developed defences against pathogens via physical, chemical, and cellular mechanisms that underlie the innate immune response and allow them to identify and neutralise invaders (Aristizábal and González, 2013). Immune regulation is an elegant dance of surveilling, protecting, and rebuilding whose imbalance can lead to long-term complications and disease. Nicotinic acetylcholine receptors (nAChR) have been shown to mediate the cholinergic anti-inflammatory pathway (CAP) which within the brain may be able to curtail microglial’s damaging phenotypes. In this brief review, we seek to highlight the emerging roles of nAChRs as modulators of microglia in neuroinflammation and associated neurodegenerative diseases.

The nAChR, named after its endogenous ligand the neurotransmitter acetylcholine (ACh) and the alkaloid nicotine, are physiological discoveries of the 20th century (Langley, 1908). The first neurotransmitter receptor to be isolated from the Torpedo electric ray (Fulpius et al., 1981), they relay messages between neurons in the central nervous system (CNS) and peripheral nervous system and modulate function at neuromuscular junctions (Rodríguez Cruz et al., 2020). The nAChR belongs to an evolutionarily conserved group of ligand-gated ion channels sharing the same Cys-loop configuration that includes the 5-hydroxytryptamine (5HT3 or serotonin), γ-aminobutyric acid type A (GABAA), and glycine receptors (GlyR).

Each nAChR is a pentamer that can be composed of various subunits such as α1 - α10, β1 - β4, γ, δ, and ε (Kalamida et al., 2007). These subunits are composed of four α-helical transmembrane segments (TM) with extracellularly located N- and C- termini (Fig. 1). Not all subunit combinations produce functional receptors, yet the arrangement of different subunits is specific to the tissue where particular nAChRs are predominantly expressed, and importantly, it determines their function and pharmacological properties (Ho et al., 2020). Such a diverse range of subtype combinations and stoichiometries offers considerable therapeutic advantage since each has a different pharmacokinetic profile and expression pattern (Ho et al., 2020).

Functional pentamers must include at least one α subunit, as critical tandem cysteine residues that bind ACh are in the α-domain. The orthosteric ligand binding site is on the N-terminal extracellular domain (ECD), the amino terminus “beginning” of the protein on the external side of the cell membrane, and the intracellular linker between the 3rd and 4th transmembrane segments (TM3-TM4 loop) contains phosphorylation sites crucial for activating intracellular signalling pathways (Miyazawa et al., 2003) (Fig.1 A). The four TM segments create an intra-subunit cavity that is thought to be a conserved modulatory allosteric site capable of binding positive allosteric modulators (PAMs) such as PNU-120596 (Young et al., 2008) (Fig.1 A).

Ion channels function as gated pores inserted in cell membranes that allow ions to flow through them in response to certain stimuli. These can be activated by diverse stimuli such as changes in the membrane potential for voltage-gated sodium (Nav), calcium (Cav), and potassium (Kv) channels; binding of a ligand in receptors activated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA), protons in acid-sensing ion channels (ASIC); or mechanically-gated such as the PIEZO channels (Martinac et al., 2020). nAChRs are classic models of ionotropic receptors, where ligand binding induces the opening of an ion-conducting pore allowing ions to flow down their electrochemical gradient across the plasma membrane, in this case, Na+ and Ca2+ flow into the cell whereas K+ flows out. Ionotropic function regulates membrane potential, neurotransmitter release, and other intracellular signalling, thus it is essential for rapid chemoelectric signal transduction throughout the nervous system (Changeux and Paas, 2009).

Kabbani et al. (2013) reviewed the dual function of nAChRs as both ionotropic and metabotropic receptors. Metabotropic receptors, also known as G protein-coupled receptors (GPCRs), are transmembrane polypeptides associated with a Gαβγ-complex capable of binding guanosine triphosphate (GTP) and activating intracellular signalling cascades (Fig. 1B). Upon receptor activation, Gα dissociates from the Gαβγ-complex, leaving the βγ-dimer free to interact laterally with other membrane proteins, and exchanges GTP for the lower energy guanosine diphosphate (GDP) using the free energy to activate intracellular signalling molecules (Li et al., 2002) (Fig. 1 C). These activities prolong calcium signalling past its ionotropic status into the desensitized state and contribute to many of the unique functions of the α7 nAChR (Kabbani & Nichols, 2018).

The GlyR is structurally similar to nAChRs which have been shown to interact with G proteins (Guzman et al., 2009). A short sequence-specific G protein binding cluster has been identified within the TM3-TM4 loop that is responsible for binding Gβγ (San Martin et al., 2012). More recently, comparisons between TM3-TM4 regions from different nAChRs and the GlyRs have highlighted regions of substantial conservation which are indicative of a focal point for interactions between nAChRs and various intracellular signalling mechanisms (Nemecz et al., 2016). Functional interactions are thought to occur with neighbouring receptors including D2 dopamine receptors and GPCRs as well as being able to functionally co-assemble with 5-HT3 receptors (Kabbani et al., 2013, van Hooft et al., 1998). The nAChR has been shown to contain ACh-independent functions, such as transduction of airborne vibration mediated by the DES-2/DEG-3 subunits that allow the nematode Caenorhabditis elegans neurons to sense sound (Iliff et al., 2021), highlighting the complex signalling process in which these proteins can be involved.

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