Targeting Neuronal Alpha7 Nicotinic Acetylcholine Receptor Upregulation in Age-Related Neurological Disorders

Abstract

The multifunctional roles of alpha7 nicotinic acetylcholine receptors (α7nAChRs), ranging from cognitive enhancement, neuroprotection, and anti-inflammatory action, credit tagging this receptor as "unique" among the cholinergic receptor family. The uniqueness of α7nAChRs in neuronal function and communication lies in their high calcium permeability among the cholinergic receptor family. The ionotropic function of α7nAChRs is governed by protein kinases' post-translational modification (PTMs), which alter their expression and function, affecting neuronal communication. A decrease in the ionotropic function of α7nAChRs and its downstream signaling pathways is observed across many neurologic disorders. The loss of α7nAChRs, decreased cholinergic function, and increased acetylcholinesterase levels are commonly associated with neuronal degeneration, cognitive impairment, and decreased memory function. An extensive body of evidence suggests the cognitive benefits of simple nutraceutical supplementation, Vitamin D3 (VD), in many neurologic disorders (Skv et al. in Mol Neurobiol 61:7211-7238, 2024). The present review will, however, focus on recent and past evidence deciphering the unique properties of α7nAChRs crucial for brain function. We have also emphasized on the therapeutic benefits of VD supplementation in restoring cholinergic neurotransmission and α7nAChRs expression in various neuropsychiatric and neurologic disorders.

Keywords: Alpha7 nicotinic acetylcholine receptor; Vitamin D receptor; Vitamin D3.

Fig. 1

Diagrammatic representation of a single subunit of α7nAChR showing amino and carboxyl terminals. M3-M4 cytoplasmic loop of the channel contains putative phosphorylation sites for protein kinases like Src kinase and protein kinase A (PKA). A functional receptor is formed by combining five subunits (shown in blue) and contain five agonist binding sites (shown in black triangles) (Komal et al. 2014, 2015)

Fig. 2

Schematic representation of α7nAChRs metabolism and neuroprotective effect of VD. Steps 1 to 4 illustrate the major steps of α7nAChRs activation from binding to the endogenous ligand, ACh, to its metabolism by AChE. (1) Acetylcholine released from presynaptic neurons activates α7nAChRs, acting as an agonist. (2) This activation increases Ca2+ permeability, leading to various neuromodulatory functions. (3) The receptor undergoes phosphorylation by various kinase enzymes, activating multiple signaling pathways. Additionally, various phosphatases (tyrosine phosphatase, serine–threonine phosphatase) boost α7nAChRs activity (not shown here). (4) Acetylcholine is metabolized by the acetylcholinesterase enzyme into acetyl-CoA and choline. (5) Vitamin D3 (cholecalciferol, VD), through VD receptors (VDRs), exerts various neuroprotective actions, including enhanced α7nAChR gene and protein expression and reduction in acetylcholine esterase (AChE) activity (Picciotto et al. ; Komal et al. ; Manjari et al. ; Skv et al. 2024). Presynaptic localization of α7nAChRs on different neurons and their high calcium permeability can directly cause neurotransmitter release and modulate neuronal excitability (Girod et al. ; Jones and Wonnacott ; SharMa et al. 2008). Abbreviations:α7nAChR alpha7 nicotinic acetylcholine receptor, PO4- phosphate ion, Ca2+  Calcium ion, PKA Protein kinase A, PKC Protein kinase C, AChE Acetylcholinesterase enzyme, VD Vitamin D3, nVDR Nuclear Vitamin D receptor, mVDR Membrane-bound Vitamin D receptor; RXR: Retinoid X receptor; VDRE: Vitamin D Response Element; BDNF: Brain-derived neurotrophic factor, NGF nerve growth factor, NT-3 Neurotrophin-3, HSP Homeostatic synaptic plasticity, mEPSC Spontaneous miniature excitatory postsynaptic currents

Fig. 3

Different attributes in neurodegenerative conditions. α7nAChRs expression and function are compromised in myriad mental disorders. VD intervention enhances cholinergic activity and rescues cognition, memory, and neurotrophin expression (Conejero-GoldBerg et al. ; Phenis et al. ; Navarro et al. ; Xu et al. ; Terry et al. 2023)