Activation of PKA is dependent on cAMP produced by the activation of one or more of the nine isoforms of adenylyl cyclase that are activated or inhibited in complex manners by G-proteins.66 All adenylyl cyclases are activated by Gαs. AC5 is activated by Gαolf ; AC2, AC4, and AC7 are activated by free Gβγ subunits released from Gi/o; and AC1, AC5, AC6, and AC8 are inhibited by Gαi/o.