Spatiotemporal Dynamics of Nicotinic Acetylcholine Receptors and Lipid Platforms

Abstract

The relationships between neurotransmitter receptors and their membrane environment are complex, mutual (bidirectional) and physiologically important. Some of these relationships are established with subsets of the membrane lipid population, in the form of lipid platforms, lateral heterogeneities of the bilayer lipid having a dynamic chemical composition distinct from that of the bulk membrane. In addition to the equilibrium between the biosynthetic production, exocytic delivery and recycling of receptors on the one hand, and the endocytic internalization on the other, lateral diffusion, clustering and anchorage of receptors at the lipid platforms play key roles in determining the amount of active receptors at the synapse. Mobile receptors traffic between reservoir non-synaptic membranes and the synapse predominantly by thermally driven Brownian motion, and become immobilized at the perisynaptic region or the synapse proper by various mechanisms. These comprise: (a) clustering mediated by homotropic inter-molecular receptor-receptor associations; (b) heterotropic associations with non-receptor scaffolding proteins or the subjacent cytoskeletal meshwork, leading to diffusional "trapping", and (c) protein-lipid interactions, particularly with the neutral lipid cholesterol. Preceded by a brief introduction on the currently used methods to study protein lateral mobility in membranes, this review assesses the contribution of some of these mechanisms to the supramolecular organization and dynamics of the paradigm neurotransmitter receptor of muscle and neuronal cells-the nicotinic acetylcholine receptor (nAChR). The translational mobility of nAChRs at these two cell surfaces differs in terms of diffusion coefficients and residence intervals at the synapse, which cover an ample range of time regimes. Neuronal α7 nAChRs exhibit diffusion coefficients similar to those of other neurotransmitter receptors and spend part of their lifetime confined to the perisynaptic region of glutamatergic (excitatory) and GABAergic (inhibitory) synapses; they may also be involved in the regulation of the dynamic equilibrium between excitation and inhibition in brain. Abbreviations αBTX α-Bungarotoxin FCS Fluorescence correlation spectroscopy FRAP Fluorescence recovery after photobleaching MSD Mean-square displacement nAChR Nicotinic acetylcholine receptor SPT Single particle tracking TIRF Total internal reflection fluorescence 9.1. Introduction 1✉ 1

Dysregulation of Neuronal Nicotinic Acetylcholine Receptor–Cholesterol Crosstalk in Autism Spectrum Disorder

“…Brain cholinergic system dysfunction has also been reported in ASD (Hardan and Handen, 2002;Eissa et al, 2018). Since nAChR function is influenced by its lipid microenvironment (see reviews in Barrantes, 2004Barrantes, , 2017 and cell-surface trafficking of nAChRs is dependent on cholesterol metabolism (Pediconi et al, 2004;Borroni et al, 2020) we explore in this review the various neurological alterations described in ASD and their possible association with an abnormal crosstalk between nAChRs and cholesterol.…”