ADCY5 targets nonmetabolic processes to alter Ca2+ responses. ADCY5 targets nonmetabolic processes to alter Ca2+ responses. A: Impaired ATP/ADP responses are only present in ADCY5-silenced islets at glucose concentrations of ≥11 mmol/L (**P < 0.01 vs. Con; two-way ANOVA; n = 9 recordings from three donors). B: Elevation of cAMP using FSK rescues ATP/ADP rises in ADCY5-silenced islets after transition from 3 mmol/L to 17 mmol/L glucose (G3-G17) (**P < 0.01 vs. shRNA; one-way ANOVA; n = 9 recordings from three donors; n = 4–5 recordings). C: ADCY5 knockdown suppresses β-cell Ca2+ responses after transition from 3 mmol/L to 8 mmol/L glucose (G3-G8) (representative traces [left panel]; gray/black, smoothed; red, raw]), as evidenced by reduced amplitude (right panel) (**P < 0.01 vs. shRNA; Mann-Whitney U test; n = 8–9 recordings from three donors). David J. Hodson et al. Diabetes 2014;63:3009-3021 ©2014 by American Diabetes Association