In a yeast two hybrid screen of mouse brain cDNA library, using the N‐terminus of human type V adenylyl cyclase (hACV) as bait, we identified G protein β2 subunit as an interacting partner. Additional yeast two hybrid assays showed that the Gβ1 subunit also interacts with the N‐terminus of hACV and human type VI adenylyl cyclase (hACVI). In‐vitro adenylyl cyclase activity assays using membranes of Sf9 cells expressing hACV or hACVI showed that Gβγ subunits enhance the activity of these enzymes in presence of Gαs or forskolin. Deletion of residues 77–151, but not 1–76, in the N‐terminus of hACVI obliterated the ability of Gβγ subunits to stimulate the enzyme. Likewise, activities of the recombinant soluble forms of ACV and ACVI, which lack the N‐termini, were not enhanced by Gβγ subunits. Transfection of the C terminus of G protein receptor kinase 2 to sequester endogenous Gβγ subunits attenuated the ability of isoproterenol to increase cAMP accumulation in COS‐7 cells overexpressing hACVI even when Gi was inactivated by pertussis toxin. Therefore, we conclude that the N‐termini of human hACV and hACVI are necessary for their interactions with, and regulation by Gβγ subunits both in‐vitro and in intact cells. Moreover, Gβγ subunits derived from source(s) other than Gi are necessary for the full activation of hACVI by isoproterenol in intact cells. Supported by NIH grants HL59679 and GM073181 to TBP and GM060419 to CWD.