Spatial and temporal control of GPCR signaling by ACs. In hippocampal neurons, CRHR1, upon binding to agonist CRH, activates the trimeric G protein complex, composed of α, β, and γ subunits. Stimulatory Gα subunit is released and activates tmAC and cAMP production (Irannejad and von Zastrow, 2014). In parallel, activated GPCR can also induce local Ca²⁺ release that activates sAC, followed by an increase in cAMP levels (Inda et al., 2016). (1) These two sources of cAMP at the PM contribute to the early phase of ERK activation via the effectors protein kinase A (PKA) and EPACs (Inda et al., 2016). Activated GPCRs once released from the G proteins are phosphorylated and recruit β-arrestin (β-ARR) to be internalized via clathrin-coated pits (CCPs; Irannejad and von Zastrow, 2014). (2) At the endosomal station, GPCRs activate sAC to trigger a second wave of cAMP production and to sustain Erk signaling in an EPAC-dependent fashion. sAC activation at the PM and at endosomes requires Ca²⁺ and bicarbonate (not depicted for simplicity; Inda et al., 2016). The signaling cascade leading to Ca²⁺ and bicarbonate release (particularly at the endosomal station) and the exact mechanism of action of sAC are not completely characterized. The different forms of ACs, and the corresponding cAMP gradients generated by them, are depicted in different colors to highlight their different roles. Whether this specificity reflects different isoforms and/or regulation remains to be clarified.