Figure 6. PKA is anchored to scaffolds that assemble macromolecular complexes and define foci for PKA signalling.
a | Cardiomyocytes are used as an example to illustrate how cyclic AMP-dependent protein kinase (PKA) can regulate different functions in a cell. PKA signalling is mediated by complexes with different subcellular localizations. Targeting and assembly of these PKA-containing complexes is mediated by A kinase anchoring proteins (AKAPs). Most AKAPs are specific for the RII regulatory subunit (blue ovals), a few have dual specificity and can bind to either RI or RII (yellow oval and dashed R subunits) and a few, such as SKIP (which functions as an AKAP), are RI regulatory subunit-specific (red oval). By binding to different regulatory subunits, AKAPs assemble complexes that regulate diverse functions. For example, in cardiomyocytes, different PKA-containing complexes can regulate Ca2+ uptake by regulating the activity of L-type Ca2+ channels located at the plasma membrane, promote the storage of Ca2+ in the sarcoplasmic reticulum by activating Ca2+ uptake pumps or its release by activating Ca2+-release channels (which are coupled to the junction–triadin–calsequestrin complex that binds Ca2+). PKA-containing complexes can also regulate cardiomyocyte contraction when localized to the cytoskeleton, where these enzyme regulate mitochondrial activity necessary for contraction. b | Assembly of PKA at the voltage gated Ca2+ channel 1.2 (CaV1.2) is mediated by AKAP5 (also known as AKAP79 in humans or AKAP150 in mice), which interacts with the plasma membrane and brings PKA in close proximity to the tail of the channel (shown in red) that harbours a target phosphorylation site and calcineurin (CaN). PKA phosphorylates and activates the channel. After that, Ca2+ enters the cell and binds to CaN and anchored calmodulin (CaM). CaN is activated in two ways by Ca2+: by binding to the calmodulin-like B-subunit of CaN and to a separate Ca2+-bound CaM. Activated CaN can then dephosphorylate the channel, decreasing its activity. Furthermore CaN dephosphorylates the RIIβ regulatory subunit of PKA, promoting its binding to the catalytic subunit and inactivation of PKA. Dephosphorylation can also be accomplished by the phosphatase PP2A, which binds directly to the channel. Targeting of the PKA holoenzyme is mediated by an amphipathic helix in the AKAP, referred to as the A kinase-binding (AKB) motif that binds with high affinity to the dimerization and docking domain (D/D domain) of RII regulatory subunits.