Comparing effects on spontaneous rate and I_f of changes in PI3K and AMPK activity. (A and B) Data from Lin et al. (2019). (A) Spontaneous rate of a dog SAN is reduced after 3h perfusion with 1 µM PI-103, a PI3K inhibitor (lower row), while no decline is seen in control conditions (upper row). (B) Top: I_f recorded from a rabbit SAN cell is reduced by external perfusion with PI-103 (middle), but returns to control levels if the cell is internally perfused with PIP3 (right). Bottom: I_f membrane density in SAN cells decreases with incubation time in the presence of PI-103. Cell infusion with PIP3, but not PI(4,5)P2 or PI(3,5)P2, rescues the I_f density to control values. **, P < 0.05 versus control.(C and D) Data from Yavari et al. (2017). SAN cells from mice carrying heterozygous (Het) or homozygous (Homo) activating mutation of γ2-AMPK (R299Q) beat at a slower rate (C) and express less funny channels (D, top) than wild-type cells. I_f membrane expression density (D, bottom left) and HCN4 expression level are ∼50% smaller in mutant that wild-type pacemaker cells (D, bottom right).***, P < 0.001 versus WT.