Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery

CORRADI J; BOUZAT C

MOLECULAR PHARMACOLOGY

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Lugar: Baltimore; Año: 2016 vol. 90 p. 288 - 299

0026-895X

The nicotinic acetylcholine receptor (nAChR) belongs to asuperfamily of pentameric ligand-gated ion channels involvedin many physiologic and pathologic processes. Among nAChRs,receptors comprising thea7 subunit are unique because of theirhigh Ca21permeability and fast desensitization. nAChR agonistselicit a transient ion flux response that is further sustained by therelease of calcium from intracellular sources. Owing to the dualionotropic/metabotropic nature of a7 receptors, signaling pathways are activated. Thea7 subunit is highly expressed in thenervous system, mostly in regions implicated in cognition andmemory and has therefore attracted attention as a novel drugtarget. Additionally, its dysfunction is associated with severalneuropsychiatric and neurologic disorders, such as schizophrenia and Alzheimer?s disease.a7 is also expressed in non-neuronalcells, particularly immune cells, where it plays a role in immunity,inflammation, and neuroprotection. Thus, a7 potentiation hasemerged as a therapeutic strategy for several neurologic andinflammatory disorders. With unique activation properties, thereceptor is a sensitive drug target carrying different potentialbinding sites for chemical modulators, particularly agonists andpositive allosteric modulators. Although macroscopic and singlechannel recordings have provided significant information aboutthe underlying molecular mechanisms and binding sites of modulatory compounds, we know just the tip of the iceberg. Furtherconcerted efforts are necessary to effectively exploita7 as a drugtarget for each pathologic situation. In this article, we focus mainlyon the molecular basis of activation and drug modulation ofa7,key pillars for rational drug design