An adenylyl cyclase-mAKAPbeta signaling complex regulates cAMP levels in cardiac myocytes.
Protein kinase A-anchoring proteins (AKAPs) play important roles in the compartmentation of cAMP signaling, anchoring protein kinase A (PKA) to specific cellular organelles and serving as scaffolds that assemble localized signaling cascades. Although AKAPs have been recently shown to bind adenylyl cyclase (AC), the functional significance of this association has not been studied. In cardiac myocytes, the muscle protein kinase A-anchoring protein beta (mAKAPbeta) coordinates cAMP-dependent, calcium, and MAP kinase pathways and is important for cellular hypertrophy. We now show that mAKAPbeta selectively binds type 5 AC in the heart and that mAKAPbeta-associated AC activity is absent in AC5 knock-out hearts. Consistent with its known inhibition by PKA phosphorylation, AC5 is inhibited by association with mAKAPbeta-PKA complexes. AC5 binds to a unique N-terminal site on mAKAP-(245-340), and expression of this peptide disrupts endogenous mAKAPbeta-AC association. Accordingly, disruption of mAKAPbeta-AC5 complexes in neonatal cardiac myocytes results in increased cAMP and hypertrophy in the absence of agonist stimulation. Taken together, these results show that the association of AC5 with the mAKAPbeta complex is required for the regulation of cAMP second messenger controlling cardiac myocyte hypertrophy.
Kapiloff
Michael S
MS
Department of Medicine, Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida 33101, USA. Mkapiloff@med.miami.edu
Piggott
Leslie A
LA
Sadana
Rachna
R
Li
Jinliang
J
Heredia
Lorena A
LA
Henson
Edward
E
Efendiev
Riad
R
Dessauer
Carmen W
CW
D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
D054758:A Kinase Anchor Proteins; C544304:Akap6 protein, mouse; C484293:Akap6 protein, rat; D007527:Isoenzymes; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V