Cell-surface translational dynamics of nicotinic acetylcholine receptors

Abstract

Synapse efficacy heavily relies on the number of neurotransmitter receptors available at a given time. 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 and clustering of receptors at the cell membrane play key roles in determining the amount of active receptors at the synapse. Mobile receptors traffic between reservoir compartments and the synapse by thermally driven Brownian motion, and become immobilized at the peri-synaptic region or the synapse by: (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. 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). Currently available information stemming from various complementary biophysical techniques commonly used to interrogate the dynamics of cell-surface components is critically discussed. The translational mobility of nAChRs at the cell surface differs between muscle and neuronal receptors in terms of diffusion coefficients and residence intervals at the synapse, which cover an ample range of time regimes. A peculiar feature of brain α7 nAChR is its ability to spend much of its time confined peri-synaptically, vicinal to glutamatergic (excitatory) and GABAergic (inhibitory) synapses. An important function of the α7 nAChR may thus be visiting the territories of other neurotransmitter receptors, differentially regulating the dynamic equilibrium between excitation and inhibition, depending on its residence time in each domain.

Boundary lipids of the nicotinic acetylcholine receptor: Spontaneous partitioning via coarse-grained molecular dynamics simulation

“…Similarly, any process that decreased total l do area while keeping the number of receptors constant would increase the local receptor density. In this model, observing increased nAChR density by adding membrane cholesterol (as in (18,(44)(45)(46)(47)(48)52,53,118) ) would be consistent with nAChR partitioning to the cholesterol-poor phase rather than the cholesterol-rich phase.…”

Isoform‐specific mechanisms of a3b4*‐nicotinic acetylcholine receptor modulation by the prototoxin lynx1

“…It is beyond the scope of the present study to determine the precise mechanisms that underlie the distinctly different kinetics of restoring (α3β4) 2 α5‐ vs . (α3β4) 2 β4‐nAChR surface expression after PI‐PLC cleavage of the lynx1 GPI anchor; however, complete restoration within 60 min may suggest a role for a rapid (α3β4) 2 α5‐nAChR internalization and recycling mechanism, as has been demonstrated for both neuromuscular and nonmuscle nAChR subtypes (60–63). This observation reinforces the previous indication that lynx1‐induced reductions in I max can primarily be attributed to a reduction in the number of cell‐surface receptors.…”

Calcium imaging with genetically encoded sensor Case12: Facile analysis of α7/α9 nAChR mutants

“…Malfunctioning of α7 receptors is associated with neurodegenerative and psychiatric diseases, chronic pain, sepsis, rheumatoid arthritis etc. [ 7 – 9 ] That is why α7 nAChRs are attracting a strong interest as a target for drug discovery and design [ 7 , 10 – 13 ], making studies of their molecular structure and functioning especially pertinent [ 14 , 15 ].…”