mAKAP and the ryanodine receptor are part of a multi-component signaling complex on the cardiomyocyte nuclear envelope

Abstract

The physical association of regulatory enzymes and ion channels at relevant intracellular sites contributes to the diversity and specificity of second messenger-mediated signal transduction in cells. mAKAP is a scaffolding protein that targets the cAMP-dependent protein kinase A and phosphodiesterase type 4D3 to the nuclear envelope of differentiated cardiac myocytes. Here we present data that the mAKAP signaling complex also includes nuclear envelope-resident ryanodine receptors and protein phosphatase 2A. The ryanodine receptor is the major cardiac ion channel responsible for calcium-induced calcium release from intracellular calcium ion stores. As demonstrated by a combination of immunohistochemistry and tissue fractionation, mAKAP is targeted specifically to the nuclear envelope, whereas the ryanodine receptor is present at both the sarcoplasmic reticulum and nuclear envelope intracellular membrane compartments. At the nuclear envelope, a subset of cardiac ryanodine receptor is bound to mAKAP and via the association with mAKAP may be regulated by protein kinase A-mediated phosphorylation. By binding protein kinase A and ryanodine receptor, mAKAP may serve as the scaffold for a cAMP- and calcium ion-sensitive signaling complex.

The Golgi apparatus is a functionally distinct Ca 2+ store regulated by the PKA and Epac branches of the β 1 -adrenergic signaling pathway

“…For example, muscle-specific A-kinase anchoring proteins (mAKAPs) form signaling complexes comprising PKA, Epac, PDE4D3, and protein phosphatase 2A (41). mAKAPs are targeted to the nuclear envelope but are also associated with RyRs in cardiomyocytes (42,43). In addition, the scaffold protein myomegalin anchors PDE4D3 to the Golgi apparatus (44), and particulate PDE3 is membrane-bound and also present in the perinuclear region (45).…”

Proteomic Studies of PP2A-B56γ1 Phosphatase Complexes Reveal Phosphorylation-Regulated Partners in Cardiac Local Signaling

“…An emerging theme in the biology of the ubiquitous phosphatase, PP2A, is that its cellular function is governed, in part, by a B subunit-mediated targeting to specific macromolecular complexes. − One such subunit in the B‘ family, B56γ1, is preferentially expressed in heart, , yet the role of the PP2A/B56γ1 heterotrimer in cardiac signaling remains largely unknown. This study exploited an unbiased affinity-based proteomic approach combined with high stringency selection to identify a discrete set of associated binding partners for B56γ1 in cardiac cells.…”

Association of PP1 with Its Regulatory Subunit AKAP149 Is Regulated by Serine Phosphorylation Flanking the RVXF Motif of AKAP149

“…However, in contrast to AKAP220 and AKAP149, Yotiao anchors PP1 in a constitutively active state toward its known substrate (44). Last, mAKAP anchors PKA, PP1 and PP2A, together with phosphodiesterase (PDE) PDE4D3 at the nuclear envelope of cardiomyocytes (45)(46)(47). PKA may phosphorylate the ryanodine receptor RyR2 and PDE4D3 at the nuclear envelope to promote ion channel activity, whereas PP2A reverses RyR2 phosphorylation (45).…”