Abstract
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 β (mAKAPβ) coordinates cAMP-dependent, calcium, and MAP kinase pathways and is important for cellular hypertrophy. We now show that mAKAPβ selectively binds type 5 AC in the heart and that mAKAPβ-associated AC activity is absent in AC5 knock-out hearts. Consistent with its known inhibition by PKA phosphorylation, AC5 is inhibited by association with mAKAPβ-PKA complexes. AC5 binds to a unique N-terminal site on mAKAP-(245-340), and expression of this peptide disrupts endogenous mAKAPβ-AC association. Accordingly, disruption of mAKAPβa-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 mAKAPβ complex is required for the regulation of cAMP second messenger controlling cardiac myocyte hypertrophy.
| Original language | English |
|---|---|
| Pages (from-to) | 23540-23546 |
| Number of pages | 7 |
| Journal | Journal of Biological Chemistry |
| Volume | 284 |
| Issue number | 35 |
| DOIs | |
| State | Published - Aug 28 2009 |
Fingerprint
ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Molecular Biology
Cite this
An adenylyl cyclase-mAKAP β signaling complex regulates cAMP levels in cardiac myocytes. / Kapiloff, Michael S; Piggott, Leslie A.; Sadana, Rachna; Li, Jinliang; Heredia, Lorena A.; Henson, Edward; Efendiev, Riad; Dessauer, Carmen W.
In: Journal of Biological Chemistry, Vol. 284, No. 35, 28.08.2009, p. 23540-23546.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - An adenylyl cyclase-mAKAP β signaling complex regulates cAMP levels in cardiac myocytes
AU - Kapiloff, Michael S
AU - Piggott, Leslie A.
AU - Sadana, Rachna
AU - Li, Jinliang
AU - Heredia, Lorena A.
AU - Henson, Edward
AU - Efendiev, Riad
AU - Dessauer, Carmen W.
PY - 2009/8/28
Y1 - 2009/8/28
N2 - 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 β (mAKAPβ) coordinates cAMP-dependent, calcium, and MAP kinase pathways and is important for cellular hypertrophy. We now show that mAKAPβ selectively binds type 5 AC in the heart and that mAKAPβ-associated AC activity is absent in AC5 knock-out hearts. Consistent with its known inhibition by PKA phosphorylation, AC5 is inhibited by association with mAKAPβ-PKA complexes. AC5 binds to a unique N-terminal site on mAKAP-(245-340), and expression of this peptide disrupts endogenous mAKAPβ-AC association. Accordingly, disruption of mAKAPβa-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 mAKAPβ complex is required for the regulation of cAMP second messenger controlling cardiac myocyte hypertrophy.
AB - 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 β (mAKAPβ) coordinates cAMP-dependent, calcium, and MAP kinase pathways and is important for cellular hypertrophy. We now show that mAKAPβ selectively binds type 5 AC in the heart and that mAKAPβ-associated AC activity is absent in AC5 knock-out hearts. Consistent with its known inhibition by PKA phosphorylation, AC5 is inhibited by association with mAKAPβ-PKA complexes. AC5 binds to a unique N-terminal site on mAKAP-(245-340), and expression of this peptide disrupts endogenous mAKAPβ-AC association. Accordingly, disruption of mAKAPβa-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 mAKAPβ complex is required for the regulation of cAMP second messenger controlling cardiac myocyte hypertrophy.
UR - http://www.scopus.com/inward/record.url?scp=69949130120&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=69949130120&partnerID=8YFLogxK
U2 - 10.1074/jbc.M109.030072
DO - 10.1074/jbc.M109.030072
M3 - Article
C2 - 19574217
AN - SCOPUS:69949130120
VL - 284
SP - 23540
EP - 23546
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 35
ER -