Activation of cAMP-Dependent PKA
Activation of cAMP-Dependent PKA
PKA (Protein Kinase-A) is a second messenger-dependent enzyme that has been implicated in a wide range of cellular processes, including transcription, metabolism, cell cycle progression and apoptosis. Known modulators of PKA activity include factors that either activate or inhibit AC (Adenylate Cyclase), resulting in an increase or decrease in cAMP (Cyclic Adenosine 3′,5′-monophosphate) levels. The enzyme occurs naturally as a four-membered structure with two regulatory (R) and two catalytic (C) subunits. Four genes encode the R subunits (RI-Alpha, RI-Beta, RII-Alpha and RII-Beta), and three encode the C subunits (C-Alpha, C-Beta and C-Gamma). Although there are major differences in the tissue distribution, biochemical and physical properties of the R subunit isoforms, differences between the various isoforms of the C subunit are more subtle. PKA is classified as a Type I or Type II enzyme depending upon the associated R subunit (i.e., RI or RII). Type I PKA is predominantly located in the cytoplasm, while Type II associates with cellular structures and organelles. Type II PKA is not a “free floating” enzyme but is anchored to specific locations within the cell by specific proteins called AKAPs (A Kinase-Anchoring Proteins). The AKAPs keep PKA localized and limit the targets that can be phosphorylated, preventing the indiscriminate phosphorylation expected from free PKA in the cytoplasm. Most AKAPs described thus far bind the RII subunits with nanomolar affinities while binding RI subunits in the micromolar range. RII-binding AKAPs range in size from 15–300kDa and are capable of binding other kinases as well as phosphatases. Anchored PKA modulates the activity of various cellular proteins, including AMPA/Kainate channels, Glutamate receptor-gated ion channels, L-type Ca2+ channels in skeletal muscle, hormone-mediated Insulin secretion in clonal beta cells, Vasopressin-mediated translocation of Aquaporin-2 into the cell membrane of renal principal cells, motility of mammalian sperm and the sperm Acrosome reaction.