One More Negative Regulator of AC6: S-Nitrosylation

In this issue of the Journal, Maghsoudi and colleagues (pp. 82–96) report a series of studies that delineate the biochemical and pharmacological mechanism of this resistance (4). The study focuses on adenylyl cyclase (AC), an enzyme crucial for pulmonary vasodilation through its action of synthesizing cAMP. There are nine isoforms of AC (AC1–AC9) that are all stimulated by Gs but otherwise are distinct in their regulatory qualities, subcellular localization, and expression profiles throughout the body (5). AC6 plays a significant role in fetal and neonatal lung, especially in pulmonary artery smooth muscle cells, where it is highly expressed. This isoform is characterized by its susceptibility to inhibition by a number of other signaling pathways, including calcium, protein kinase A, protein kinase C, and nitric oxide (NO) (6). AC6 is efficiently regulated by several G protein–coupled receptors by virtue of its colocalization in lipid raft microdomains of the plasma membrane of many cells (7).