PT - JOURNAL ARTICLE AU - Justin R King AU - Aman Ullah AU - Ellen Bak AU - Saleet Jafri AU - Nadine Kabbani TI - Ionotropic and metabotropic mechanisms of allosteric modulation of α7 nicotinic receptor intracellular calcium AID - 10.1124/mol.117.111401 DP - 2018 Jan 01 TA - Molecular Pharmacology PG - mol.117.111401 4099 - http://molpharm.aspetjournals.org/content/early/2018/03/27/mol.117.111401.short 4100 - http://molpharm.aspetjournals.org/content/early/2018/03/27/mol.117.111401.full AB - The pharmacological targeting of the α7 nicotinic acetylcholine receptor (α7) is a promising strategy in the development of new drugs for neurological diseases Because α7 receptors regulate cellular calcium, we investigated how the prototypical type II positive allosteric modulator PNU120596 affects α7 mediated calcium signaling. Live imaging experiments show that PNU120596 augments ryanodine receptor driven calcium-induced calcium release (CICR), IP3 induced calcium release (IICR), and PLC activation by the α7 receptor. Influx of calcium through the α7 channel was necessary for the effects of PNU120596 but so was the binding of G proteins in the intracellular domain of the α7 receptor as evidenced by findings using calcium chelation, α7D44A, or α7345-8A mutant expression, respectively. Spatiotemporal stochastic modeling of calcium transient responses corroborates these results and indicates that α7 receptor activation enables calcium microdomains locally and to lesser extent in the distant cytosol. From the model, PNU120596 driven modulation of the receptor activates CICR locally via ryanodine receptors, and augments IICR through enhanced channel conductance due to prolonged α7 nAChR opening. These findings provide a new mechanistic framework for understanding the effect of α7 receptor allosteric modulation on both local and global cellular calcium dynamics.