Dynamic regulation of cAMP synthesis through anchored PKA-adenylyl cyclase V/VI complexes.
Spatiotemporal organization of cAMP signaling begins with the tight control of second messenger synthesis. In response to agonist stimulation of G protein-coupled receptors, membrane-associated adenylyl cyclases (ACs) generate cAMP that diffuses throughout the cell. The availability of cAMP activates various intracellular effectors, including protein kinase A (PKA). Specificity in PKA action is achieved by the localization of the enzyme near its substrates through association with A-kinase anchoring proteins (AKAPs). Here, we provide evidence for interactions between AKAP79/150 and ACV and ACVI. PKA anchoring facilitates the preferential phosphorylation of AC to inhibit cAMP synthesis. Real-time cellular imaging experiments show that PKA anchoring with the cAMP synthesis machinery ensures rapid termination of cAMP signaling upon activation of the kinase. This protein configuration permits the formation of a negative feedback loop that temporally regulates cAMP production.
Bauman
Andrea L
AL
Howard Hughes Medical Institute, Vollum Institute, L-474, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239, USA.
Soughayer
Joseph
J
Nguyen
Bao T
BT
Willoughby
Debbie
D
Carnegie
Graeme K
GK
Wong
Wei
W
Hoshi
Naoto
N
Langeberg
Lorene K
LK
Cooper
Dermot M F
DM
Dessauer
Carmen W
CW
Scott
John D
JD
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology; D000262:Adenylyl Cyclases / Q000378:metabolism*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism* / Q000502:physiology; D004789:Enzyme Activation; D025461:Feedback, Physiological; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008954:Models, Biological; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology
D054758:A Kinase Anchor Proteins; C487775:AKAP5 protein, human; D048868:Adaptor Proteins, Signal Transducing; D007527:Isoenzymes; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; C419510:adenylyl cyclase type V