Ionotropic and Metabotropic Mechanisms of Allosteric Modulation of α 7 Nicotinic Receptor Intracellular Calcium

• Published in: Molecular pharmacology 2018-06, Vol.93 (6), p.601
• Main Authors: King, Justin R, Ullah, Aman, Bak, Ellen, Jafri, M Saleet, Kabbani, Nadine
• Format: Article
• Language: English
• Subjects: alpha7 Nicotinic Acetylcholine Receptor - metabolism; Animals; Calcium - metabolism; Calcium Signaling - drug effects; Calcium Signaling - physiology; Cell Line, Tumor; Cytoplasm - metabolism; GTP-Binding Proteins - metabolism; Humans; Isoxazoles - pharmacology; PC12 Cells; Phenylurea Compounds - pharmacology; Rats
• ISSN: 1521-0111
• DOI: 10.1124/mol.117.111401

The pharmacological targeting of the 7 nicotinic acetylcholine receptor ( 7) is a promising strategy in the development of new drugs for neurologic diseases. Because 7 receptors regulate cellular calcium, we investigated how the prototypical type II-positive allosteric modulator PNU120596 affects 7-mediated calcium signaling. Live imaging experiments show that PNU120596 augments ryanodine receptor-driven calcium-induced calcium release (CICR), inositol-induced calcium release (IICR), and phospholipase C activation by the 7 receptor. Both influx of calcium through the 7 nicotinic acetylcholine receptor (nAChR) channel as well as the binding of intracellular G proteins were involved in the effect of PNU120596 on intracellular calcium. This is evidenced by the findings that chelation of extracellular calcium, expression of 7 or 7 mutant subunits, or blockade of calcium store release compromised the ability of PNU120596 to increase intracellular calcium transients generated by 7 ligand activation. Spatiotemporal stochastic modeling of calcium transient responses corroborates these results and indicates that 7 receptor activation enables calcium microdomains locally and to lesser extent in the distant cytosol. From the model, allosteric modulation of the receptor activates CICR locally via ryanodine receptors and augments IICR through enhanced calcium influx due to prolonged 7 nAChR opening. These findings provide a new mechanistic framework for understanding the effect of 7 receptor allosteric modulation on both local and global calcium dynamics.