Isoform-specific regulation of adenylyl cyclase by protein kinases that are activated by Gαi/o-coupled GPCRs. One of the proposed mechanisms for heterologous sensitization is that the phosphorylation state of the adenylyl cyclase is modified due to prolonged activation of Gαi/o-coupled receptors. Activation of inhibitory GPCRs leads to active Gαi/o and Gβγ subunits that can activate PKC, which phosphorylates and activates AC1, AC2, and AC5. Activation of Gαi/o inhibits PKA, leading to disinhibition of AC5 and AC6. Gβγ subunits can also activate Raf-1, which phosphorylates and activates AC2, AC5, and AC6.