TYPE-I AND TYPE-VIII ADENYLYL CYCLASES CONSTITUTE A FAMILY WHOSE ACTIVATION IS COUPLED TO CELLULAR-DEFORMATION THROUGH THE ACTION OF CALCIUM-CALMODULIN

In certain tissues and cells, increases in concentrations of the secon d messenger cAMP are seen in response to mechanical or deformational s timuli. Type I and type VIII adenylyl cyclases, representing members o f a family of calcium-calmodulin-stimulated adenylyl cyclases, and typ e VII adenylyl cyclase were each stably expressed in human embryonal k idney (HEK) 293 cells. HEK 293 cells exogenously expressing either typ e I adenylyl cyclase or any one of three type VIII adenylyl cyclase sp lice variants respond to swelling with increases in cAMP, requiring th e presence of calcium in the extracellular medium for such responsiven ess. Type VII expressing HEK 293 cells failed to respond to swelling w ith increased cAMP but demonstrated potentiation of isoproterenol-stim ulated activity. This is characteristic of the influence of protein ki nase C on the activity of the type VII protein. The relative swelling responsiveness of HEK 293 cells expressing splice variants of the type VIII adenylyl cyclase is consistent with the relative EC(50) values f or calcium-calmodulin stimulation of these splice variants. This is co nsistent with the involvement of calmodulin and the requirement for in creases in intracellular calcium in mediating swelling-induced acceler ation of type VIII adenylyl cyclase activity.