Myomegalin is a novel A-kinase anchoring protein involved in the phosphorylation of cardiac myosin binding protein C

Uys, G.M.; Ramburan, Amsha; Loos, Ben; Kinnear, Craig; Korkie, Lundi; Mouton, Jomien; Riedemann, Johann; Moolman‐Smook, Johanna C.

doi:10.1186/1471-2121-12-18

Cited by 52 publications

(37 citation statements)

References 29 publications

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“…Over the last years several AKAPs have been shown to associate with the sarcomere. These include synemin, which can be recruited to the Z-disc (25,95); myospryn, which localizes at the peripheral Z-disc/costameric region (92); cardiac troponin T (cTnT) (109); and myomegalin, which is proposed to regulate the phosphorylation of cMyBP-C (112). Future experiments will need to determine whether these AKAPs anchor PKA to modulate sarcomere contraction.…”

Section: Akaps and Myofiber Contractilitymentioning

confidence: 99%

A-kinase anchoring proteins: scaffolding proteins in the heart

Diviani

Dodge‐Kafka

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

101

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The pleiotropic cyclic nucleotide cAMP is the primary second messenger responsible for autonomic regulation of cardiac inotropy, chronotropy, and lusitropy. Under conditions of prolonged catecholaminergic stimulation, cAMP also contributes to the induction of both cardiac myocyte hypertrophy and apoptosis. The formation of localized, multiprotein complexes that contain different combinations of cAMP effectors and regulatory enzymes provides the architectural infrastructure for the specialization of the cAMP signaling network. Scaffolds that bind protein kinase A are called “A-kinase anchoring proteins” (AKAPs). In this review, we discuss recent advances in our understanding of how PKA is compartmentalized within the cardiac myocyte by AKAPs and how AKAP complexes modulate cardiac function in both health and disease.

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Section: Akaps and Myofiber Contractilitymentioning

confidence: 99%

A-kinase anchoring proteins: scaffolding proteins in the heart

Diviani

Dodge‐Kafka

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

101

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“…Ablation of this gene in mice leads to PKA hyperphosphorylation of RyR2 and increased sensitivity to exercise-induced arrhythmias (Lehnart et al, 2005). PDE4D is also localized to other compartments of the cardiomyocyte, including the sarcomeric region, via anchoring to myomegalin (Verde et al, 2001), an A-kinase anchoring protein (AKAP) (Uys et al, 2011), the perinuclear region by an association with mAKAP (also known as AKAP6) (Dodge et al, 2001) and to the sarcolemmal region, where PDE4D3 is recruited to the cardiac K + channel via AKAP9 (Terrenoire et al, 2009). PDE4D also associates with the PLB-SERCA complex and regulates the SERCA pump activity in the mouse heart (Beca et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

PDE4B mediates local feedback regulation of β1-adrenergic cAMP signaling in a sarcolemmal compartment of cardiac myocytes

Mika

Richter

Westenbroek

et al. 2014

Journal of Cell Science

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Multiple cAMP phosphodiesterase (PDE) isoforms play divergent roles in cardiac homeostasis but the molecular basis for their nonredundant function remains poorly understood. Here, we report a novel role for the PDE4B isoform in b-adrenergic (bAR) signaling in the heart. Genetic ablation of PDE4B disrupted bAR-induced cAMP transients, as measured by FRETsensors, at the sarcolemma but not in the bulk cytosol of cardiomyocytes. This effect was further restricted to a subsarcolemmal compartment because PDE4B regulates b 1 AR-, but not b 2 AR-or PGE2-induced responses. The spatially restricted function of PDE4B was confirmed by its selective effects on PKA-mediated phosphorylation patterns. PDE4B limited the PKA-mediated phosphorylation of key players in excitationcontraction coupling that reside in the sarcolemmal compartment, including L-type Ca 2+ channels and ryanodine receptors, but not phosphorylation of distal cytosolic proteins. b 1 AR-but not b 2 ARligation induced PKA-dependent activation of PDE4B and interruption of this negative feedback with PKA inhibitors increased sarcolemmal cAMP. Thus, PDE4B mediates a crucial PKAdependent feedback that controls b 1 AR-dependent cAMP signals in a restricted subsarcolemmal domain. Disruption of this feedback augments local cAMP/PKA signals, leading to an increased intracellular Ca 2+ level and contraction rate.

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“…Alignments of the coding sequence (middle, boxed) and translated peptide encoded by exon 4c show that either nontriplet indels have generated new codons or, for some unknown reason, the nucleotide substitution rate is accelerated in this exon. cyclic nucleotide phosphodiesterase (Verde et al 2001) and A-kinase (Uys et al 2011) in vertebrate muscles. Additionally, these proteins share no significant homology outside of the KFC motif and flanking domain, each has unique motifs and domains not present in the other proteins, and removal of the KFC motif for BLAST searches returns a completely different set of "best hits."…”

Section: Discussionmentioning

confidence: 99%

Probing the Boundaries of Orthology: The Unanticipated Rapid Evolution ofDrosophila centrosomin

Eisman

2013

Genetics

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The rapid evolution of essential developmental genes and their protein products is both intriguing and problematic. The rapid evolution of gene products with simple protein folds and a lack of well-characterized functional domains typically result in a low discovery rate of orthologous genes. Additionally, in the absence of orthologs it is difficult to study the processes and mechanisms underlying rapid evolution. In this study, we have investigated the rapid evolution of centrosomin (cnn), an essential gene encoding centrosomal protein isoforms required during syncytial development in Drosophila melanogaster. Until recently the rapid divergence of cnn made identification of orthologs difficult and questionable because Cnn violates many of the assumptions underlying models for protein evolution. To overcome these limitations, we have identified a group of insect orthologs and present conserved features likely to be required for the functions attributed to cnn in D. melanogaster. We also show that the rapid divergence of Cnn isoforms is apparently due to frequent coding sequence indels and an accelerated rate of intronic additions and eliminations. These changes appear to be buffered by multi-exon and multi-reading frame maximum potential ORFs, simple protein folds, and the splicing machinery. These buffering features also occur in other genes in Drosophila and may help prevent potentially deleterious mutations due to indels in genes with large coding exons and exon-dense regions separated by small introns. This work promises to be useful for future investigations of cnn and potentially other rapidly evolving genes and proteins.A S the genomic era advances, molecular biology has shifted from single-gene studies to global analyses of genomes from a broad phylogenetic range of organisms. For single-gene and global studies, a critical first step for molecular biologists is the accurate identification of orthologous genes. The concept of orthology was introduced by Fitch to differentiate between orthologous genes, which have a oneto-one relationship between species, and paralogous genes, which result from a duplication event of the original ortholog within a species (Fitch 1970(Fitch , 2000. Because orthologs are often more closely related than paralogs, it is generally assumed that gene function is likely to be conserved. Since the functional annotation of uncharacterized genomes is generally computationally based on overall sequence identity with known genes from model organisms, it is essential for orthology assignments to be accurate (Hulsen et al. 2006). The importance of orthology is made evident both by the number of databases reporting orthologous gene sets and by the number of terms introduced to describe relational subcategories in the time since Fitch initially introduced the concept of orthologous and paralogous gene relationships.Since orthologous genes are related by descent and orthology is based on sequence homology and phylogeny, the process of identification should be relatively simple. Thi...

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Myomegalin is a novel A-kinase anchoring protein involved in the phosphorylation of cardiac myosin binding protein C

Cited by 52 publications

References 29 publications

A-kinase anchoring proteins: scaffolding proteins in the heart

A-kinase anchoring proteins: scaffolding proteins in the heart

PDE4B mediates local feedback regulation of β1-adrenergic cAMP signaling in a sarcolemmal compartment of cardiac myocytes

Probing the Boundaries of Orthology: The Unanticipated Rapid Evolution ofDrosophila centrosomin

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