Adenylyl cyclase 6 defines a distinct cAMP compartment that increases somatostatin expression by airway smooth muscle cells

Abstract

All adenylyl cyclases (AC) catalyze synthesis of cAMP, but the 9 isoforms differ in localization, regulation and interactions with other signaling molecules. Human bronchial smooth muscle cells (hBSMC) express AC isoforms 2, 4, and 6. Distinct pools of cAMP maintained by AKAPs/PDEs allow cells to respond differently to activation of various GPCR/ACs. Our goal was to examine AC isoform‐specific effects on gene expression. We overexpressed AC2 (non‐raft localized isoform) or AC6 (lipid raft localized isoform) in hBSMC. A PCR array showed a number of genes that were differentially regulated when AC2 or AC6 were overexpressed and activated by forskolin (Fsk). AC6 increased Fsk‐stimulated expression of somatostatin (SST), while overexpression of AC2 led to Fsk‐induced SST mRNA levels below control cells. Activation of Gs coupled GPCR induced SST expression to levels greater than Fsk, suggesting that GPCR might also invoke a non‐cAMP pathway. βAR‐induced SST expression was similar in control cells and those overexpressing AC2 or AC6, while EP2R‐induced SST expression was enhanced by overexpression of AC6 but not AC2. Overexpression of either AC increased Fsk‐stimulated cAMP, but receptor‐stimulated cAMP levels differed between AC2 and AC6. cAMP driven SST expression appears to be coupled to AC6, but not AC2, illustrating that cAMP compartments differentially regulate gene expression. Supported by HL079166.