A glia-derived acetylcholine-binding protein that modulates synaptic transmission

Abstract

There is accumulating evidence that glial cells actively modulate neuronal synaptic transmission. We identified a glia-derived soluble acetylcholine-binding protein (AChBP), which is a naturally occurring analogue of the ligand-binding domains of the nicotinic acetylcholine receptors (nAChRs). Like the nAChRs, it assembles into a homopentamer with ligand-binding characteristics that are typical for a nicotinic receptor; unlike the nAChRs, however, it lacks the domains to form a transmembrane ion channel. Presynaptic release of acetylcholine induces the secretion of AChBP through the glial secretory pathway. We describe a molecular and cellular mechanism by which glial cells release AChBP in the synaptic cleft, and propose a model for how they actively regulate cholinergic transmission between neurons in the central nervous system.

Nicotinic receptor signaling in nonexcitable cells

“…The sequence of the AChBP reveals homology to the ␣7 class of nAChRs. From binding studies, the AChBP has a high affinity for both ␣Bgt and nicotine (Smit et al, 2001).…”

“…Perhaps the most unusual potential role for glial nAChRs comes from a recent study on synaptic transmission in CNS neurons of the snail Lymnaea stagnalis (Smit et al, 2001). Glial cells in the snail synthesize and exocytose nAChR fragments containing the ligand binding domains, assembled in a pentamer.…”

Regulatory mechanisms that govern nicotinic synapse formation in neurons

“…Of particular interest for interneuronal nicotinic synapses, glia express nAChRs, albeit at low levels relative to neurons, respond to ACh with intracellular calcium fluxes, and may release ACh (Villegas, 1972;Lieberman et al, 1989;Rogers et al, 2001;Sharma and Vijayaraghavan, 2001;Araque et al, 2002). Further, perisynaptic glial cells of the molluscan cholinergic synapse respond to ACh by releasing a soluble ACh-binding protein that may modulate synaptic transmission (Smit et al, 2001). These interesting studies suggest the novel concept that glia actively function as important regulatory and modulatory influences at interneuronal nicotinic synapses (see review by S.Vijayaraghavan, this issue).…”

Structure-guided drug design: Conferring selectivity among neuronal nicotinic receptor and acetylcholine-binding protein subtypes

“…Sixma and colleagues have characterized pharmacologically and structurally a soluble protein, the acetylcholine binding protein (AChBP) from the fresh water snail, Lymnaea stagnalis, whose subunits are homologous to the extracellular domain of the nicotinic receptor. This soluble pentameric protein from Lymnaea, the related proteins from Bulinus, and the marine species, Aplysia, bind nicotinic ligands with the requisite specificity [6,7]. When the gene encoding an AChBP is coupled to a sequence encoding the transmembrane spans of the ligand-gated ion channel family, the expressed protein shows the capacity to gate ions when elicited by agonists, in a fashion expected for a receptor composed of the so derived expressed subunit chimera [8].…”