Kinetic properties of Ca2+/calmodulin-dependent phosphodiesterase isoforms dictate intracellular cAMP dynamics in response to elevation of cytosolic Ca2+.

Multiply regulated adenylyl cyclases (AC) and phosphodiesterases (PDE) can yield complex intracellular cAMP signals. Ca2+-sensitive ACs have received far greater attention than the Ca2+/calmodulin-dependent PDE (PDE1) family in governing intracellular cAMP dynamics in response to changes in the cytosolic Ca2+ concentration ([Ca2+]i). Here, we have stably expressed two isoforms of PDE1, PDE1A2 and PDE1C4, in HEK-293 cells to determine whether they exert different impacts on cellular cAMP.

Ca2+-calmodulin-dependent phosphodiesterase (PDE1): current perspectives.

Ca2+-calmodulin-dependent phosphodiesterases (PDE1), like Ca2+-sensitive adenylyl cyclases (AC), are key enzymes that play a pivotal role in mediating the cross-talk between cAMP and Ca2+ signalling. Our understanding of how ACs respond to Ca2+ has advanced greatly, with significant breakthroughs at both the molecular and functional level. By contrast, little is known of the mechanisms that might underlie the regulation of PDE1 by Ca2+ in the intact cell.

Sustained entry of Ca2+ is required to activate Ca2+-calmodulin-dependent phosphodiesterase 1A.

Regulation of adenylyl cyclases (ACs) by Ca2+ requires capacitative Ca2+ entry (CCE) (Cooper, D. M. F.

Parathyroid hormone increases the sensitivity of inositol trisphosphate receptors by a mechanism that is independent of cyclic AMP.

1 In fura 2-loaded HEK-293 cells stably expressing human type 1 parathyroid hormone (PTH) receptors, PTH potentiated the Ca(2+) mobilization evoked by carbachol by >4 fold without itself increasing the intracellular [Ca(2+)]. 2 PTH potentiated the Ca(2+) release evoked by a cell-permeant analogue of inositol 1,4,5-trisphosphate (InsP(3)BM). 3 Prolonged incubation with InsP(3)BM emptied the Ca(2+) stores as effectively as PTH in combination with a maximal concentration of carbachol, indicating that PTH did not increase the size of the InsP(3)-sensitive Ca(2+) pool.