Type I and type VIII adenylyl cyclases constitute a family whose activation is coupled to cellular deformation through the action of calcium–calmodulin

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Abstract
In certain tissues and cells, increases in concentrations of the second messenger cAMP are seen in response to mechanical or deformational stimuli. Type I and type VIII adenylyl cyclases, representing members of a family of calcium–calmodulin-stimulated adenylyl cyclases, and type VII adenylyl cyclase were each stably expressed in human embryonal kidney (HEK) 293 cells. HEK 293 cells exogenously expressing either type I adenylyl cyclase or any one of three type VIII adenylyl cyclase splice variants respond to swelling with increases in cAMP, requiring the presence of calcium in the extracellular medium for such responsiveness. Type VII expressing HEK 293 cells failed to respond to swelling with increased cAMP but demonstrated potentiationof isoproterenol-stimulated activity. This is characteristic of the influence of protein kinase 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 EC50values for calcium–calmodulin stimulation of these splice variants. This is consistent with the involvement of calmodulin and the requirement for increases in intracellular calcium in mediating swelling-induced acceleration of type VIII adenylyl cyclase activity.Key words: mechanotransduction, cAMP, calcium, calmodulin, cytoskeleton.