Slow‐channel mutation in acetylcholine receptor αM4 domain and its efficient knockdown

Abstract

alphaC418W occurring in humans causes a slow-channel syndrome by enhancing the relative stability of the channel open state. Efficient and selective knockdown of the mutant allele holds promise of therapeutic gene silencing.

Lateral Diffusion, Function, and Expression of the Slow Channel Congenital Myasthenia Syndrome αC418W Nicotinic Receptor Mutation with Changes in Lipid Raft Components

“…Slow channel congenital myasthenia syndromes (SCCMS) are a group of genetic disorders of neuromuscular transmission characterized by a progressive degeneration of the neuromuscular junction and muscle atrophy leading to fatigability and weakness. The novel SCCMS nAChR mutant ␣C418W is the first lipid-exposed mutation identified in a patient (7).…”

Molecular mechanisms of acetylcholine receptor–lipid interactions: from model membranes to human biology

“…Side chains of residues forming part of the agonist-binding site (αTrp149) and the channel gate (αLeu251, as well as analogous β-, γ-and δ-subunit leucines) are shown in blue and tan, respectively. A Cys residue at the lipid-protein interface of α-TM4, whose mutation to Trp in the muscle-type nAChR leads to biological consequences (Shen et al 2006), is highlighted in yellow. Views from the synaptic cleft are shown on the right for the agonist-binding (top) and transmembrane pore domains (bottom) with color coding to highlight the different subunits (α, red; β, blue; γ, purple, and δ, green)…”

“…humans (Shen et al 2006). The non-competitive antagonist, promegestone likely interacts at the interface between M4 and M1+M3 (Blanton et al 1999).…”

“…These receptors mediate inter-cellular communication at the neuromuscular junction and neuronal synapses, and are implicated in a variety of physiological processes including voluntary motion, memory, attention, sleep, wakefulness, reward (nicotine), and pain. While the lipid sensitivities of most mammalian nAChRs are unknown, a genetic mutation that alters the lipidprotein interface of the muscle-type nAChR leads to changes in nAChR gating with profound effects on human biology (Shen et al 2006). The exquisite lipid sensitivity of the Torpedo nAChR and the demonstrated effects of altered nAChRlipid interactions on human biology suggest that subtle variations in the nAChR-lipid micro-environment could play an important role modulating synaptic communication.…”

Aromaticity at the Water-Hydrocarbon Core Interface of the Membrane: Consequences on the Nicotinic Acetylcholine Receptor

“…lipid-protein interactions at the WHc interface, because of existing knowledge of channel structure, gating mechanics and the overall spatial orientation of the lipid exposed domains. [21][22][23][24][25][26][27] We introduced a series of amino acid substitutions by site-directed mutagenesis at the position phenylalanine 426 (F426) in the M4 domain of the alpha subunit ( Figs. 1 and 2).…”