REVIEWThe mAKAP signaling complex: Integration of cAMP, calcium, and MAP kinase signaling pathways
Introduction
Over 30 years ago, a seminal observation was made that treatment of cardiac myocytes with norepinephrine, but not prostaglandin E1, stimulated contraction and glycogen metabolism (Keely, 1977, Keely, 1979). Since both hormones increased the concentration of the second messenger cAMP and activated the cAMP-dependent protein kinase (PKA), it was hypothesized that spatially restricted microdomains of cAMP allowed for these differential hormonal affects. At first, this theory of cAMP compartmentation was controversial because cAMP was considered to be freely diffusible in the cytosol and no structural determinants for compartmentation were known (Bacskai et al., 1993). However, several reports using both whole-cell patch/clamp recordings and live-cell imaging of cardiac myocytes clearly demonstrated that localized pools of cAMP are responsible for the activation of a sub-population of cAMP effectors, suggesting that the actions of cAMP are both spatially and temporally restricted (Jurevicius and Fischmeister, 1996; Zaccolo and Pozzan, 2002). Therefore, the molecular mechanisms of cAMP localization are of considerable interest and include the compartmentation of the regulators of cAMP concentration with the effectors of cAMP actions through the association with scaffolding proteins (Kapiloff, 2002; Zaccolo et al., 2002). Of particular interest are the A kinase-anchoring proteins (AKAPs), scaffolding proteins that directly bind PKA and focus the actions of the kinase to specific locations in the cell (Colledge and Scott, 1999). This review focuses on how a heart-enriched AKAP maintains a microdomain of cAMP near the nuclear envelope in cardiac myocytes by regulating the activity of the phosphodiesterase PDE4D3.
Section snippets
The nuclear envelope-targeted scaffold mAKAP
The scaffolding protein mAKAP is a 250-kDa PKA-binding partner located at the nuclear envelope in differentiated cardiac myocytes (Kapiloff et al., 1999). As of today, the mAKAP complex in myocytes consists of PKA, the phosphodiesterase PDE4D3, the Ca2+-activated, Ca2+ channel ryanodine receptor (RyR), the phosphatases PP2A and calcineurin, the high-molecular-weight MAP kinase ERK5, the upstream activator of ERK5 MEK5, and Epac, a guanine nucleotide exchange protein for Rap activated by cAMP (
mAKAP integrates cAMP with calcium signaling
The first target of mAKAP-bound PKA identified was the calcium-activated calcium release channel RyR (Kapiloff et al., 2001; Marx et al., 2000; Ruehr et al., 2003). This channel is found on both the sarcoplasmic reticulum (SR) and the nuclear envelope in cardiac and skeletal muscle and is responsible for the calcium-induced release of calcium from intracellular stores into the cytosol and nucleus (Bootman et al., 2000). Phosphorylation of the RyR by PKA increases the calcium sensitivity of the
PDE4D3 association influences the activity of anchored PKA
Perhaps one of the more interesting partners in the mAKAP complex is the phosphodiesterase PDE4D3 (Dodge et al., 2001). As a primary participant in cyclic nucleotide metabolism, PDE4D3 should serve to reduce local cAMP levels and to limit the amount of cAMP that may diffuse away from the nuclear envelope. In a screen for AKAPs that bind phosphodiesterases, we determined that PDE4D3, a Rolipram-sensitive, type-4D phosphodiesterase of approximately 100 kDa, specifically co-immunoprecipitated with
mAKAP orchestrates cross-talk between cAMP and MAP kinase signaling
In addition to PKA, PDE4D3 is also regulated by members of the MAP kinase family, and ERK phosphorylation of PDE4D3 serine 579 decreases phosphodiesterase activity (Hoffmann et al., 1999). We predicted that mAKAP might also anchor a MAP kinase signaling module to counteract the PKA-induced stimulation of PDE4D3. This hypothesis was confirmed when stimulation of ERK activity in rat neonatal ventricular myocytes decreased the activity of the mAKAP-associated phosphodiesterase without decreasing
cAMP modulation of ERK5 signaling
Many investigators have demonstrated cell-dependent cross-talk between cAMP and growth factor signaling. For example, cAMP stimulates ERK activity in neuronally derived cell lines, but inhibits activation of ERK in certain fibroblast and kidney cells (Cook and McCormick, 1993; Vaillancourt et al., 1994). The association of ERK5, PDE4D3 and PKA in the mAKAP complex suggests a mechanism not only for stimulation of cAMP signaling by ERK, but also the possibility of regulation of ERK5 activity by
Regulation of cardiac hypertrophy by the mAKAP complex
Several recent papers have demonstrated that activation of the cytokine gp130 receptor by leukemia inhibitory factor (LIF) induces cardiac hypertrophy through the ERK5 signaling pathway (Nicol et al., 2001). The hypertrophic effects of LIF are blocked by activation of Epac, suggesting the physiological importance of the cAMP-mediated inhibition of mAKAP-bound ERK5 detailed above (Dodge-Kafka et al., 2005). Importantly, mAKAP expression is required for LIF-induced myocyte hypertrophy (
References (32)
- et al.
AKAPs: from structure to function
Trends Cell Biol.
(1999) - et al.
Targeting of PKA to glutamate receptors through a MAGUK–AKAP complex
Neuron
(2000) - et al.
NFAT signaling: choreographing the social lives of cells
Cell
(2002) - et al.
AKAP79 and the evolution of the AKAP model
FEBS Lett.
(2000) - et al.
ERK2 mitogen-activated protein kinase binding, phosphorylation, and regulation of the PDE4D cAMP-specific phosphodiesterases. The involvement of COOH-terminal docking sites and NH2-terminal UCR regions
J. Biol. Chem.
(2000) - et al.
PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts
Cell
(2000) - et al.
Cloning and characterization of A-kinase anchor protein 100 (AKAP100): a protein that targets A-kinase to the sarcoplasmic reticulum
J. Biol. Chem.
(1995) - et al.
Targeting of protein kinase A by muscle A kinase-anchoring protein (mAKAP) regulates phosphorylation and function of the skeletal muscle ryanodine receptor
J. Biol. Chem.
(2003) - et al.
Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP-dependent protein kinase
J. Biol. Chem.
(1996) - et al.
Compartmentalisation of cAMP and Ca2+ signals
Curr. Opin. Cell Biol.
(2002)
Spatially resolved dynamics of cAMP and protein kinase A subunits in Aplysia sensory neurons
Science
Cardiac excitation–contraction coupling
Nature
Nuclear calcium signaling
Cell. Mol. Life Sci.
Epac: a new cAMP target and new avenues in cAMP research
Nat. Rev. Mol. Cell Biol.
PKA phosphorylation of PDE4D3 facilitates recruitment of the mAKAP signaling complex
Biochem. J.
Inhibition by cAMP of Ras-dependent activation of Raf
Science
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