Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Biochem Soc Trans
2014 Apr 01;422:295-301. doi: 10.1042/BST20130264.
Show Gene links
Show Anatomy links
The cAMP-binding Popdc proteins have a redundant function in the heart.
Brand T
,
Simrick SL
,
Poon KL
,
Schindler RF
.
???displayArticle.abstract???
Popdc (Popeye-domain-containing) genes encode membrane-bound proteins and are abundantly present in cardiac myocytes and in skeletal muscle fibres. Functional analysis of Popdc1 (Bves) and Popdc2 in mice and of popdc2 in zebrafish revealed an overlapping role for proper electrical conduction in the heart and maintaining structural integrity of skeletal muscle. Popdc proteins mediate cAMP signalling and modulate the biological activity of interacting proteins. The two-pore channel TREK-1 interacts with all three Popdc proteins. In Xenopus oocytes, the presence of Popdc proteins causes an enhanced membrane transport leading to an increase in TREK-1 current, which is blocked when cAMP levels are increased. Another important Popdc-interacting protein is caveolin 3, and the loss of Popdc1 affects caveolar size. Thus a family of membrane-bound cAMP-binding proteins has been identified, which modulate the subcellular localization of effector proteins involved in organizing signalling complexes and assuring proper membrane physiology of cardiac myocytes.
Figure 1. Model of Popdc proteins and expression of Popdc1 in the heart(A) Working model of Popdc proteins. The Popdc protein is found as a dimer in cells and consists of a short extracellular domain, which is subject to glycosylation, three transmembrane domains and a conserved Popeye domain in the intracellular part of the protein. The C-terminus is variable in length and subject to alternative splicing. aa, amino acids. (B–E) Immunohistochemical detection of Popdc1 in the adult mouse heart. Sections were counterstained with DAPI to label the nuclei. (B) Expression of Popdc1 in cardiac myocytes. Fat arrow, intercalated disc; thin arrow, lateral membrane; small arrow, t-tubules. (C and D) Lack of Popdc1 expression in the epicardium and subepicardium (arrow in C) and in coronary arteries (arrow in D). (E–G) The expression levels of Popdc1 in the atrioventricular node (AVN) and His bundle (His) are higher than in the ventricular septum (VS) and equal to the level in the atria (AT). Immunohistochemical staining of mouse hearts using antibodies directed against (E) Popdc1 and (F) HCN4 (hyperpolarization activated cyclic nucleotide-gated potassium channel 4). (G) Merge of Popdc1 and HCN4 staining.
Figure 2. Evolution of the Popdc gene family(A) Animal phyla for which genomic sequences encoding Popdc proteins are present in the NCBI or Ensembl databases are boxed in red. (B) Phylogenetic dendrogram of Popdc protein sequences. Vertebrate Popdc proteins cluster in two groups: Popdc1 and Popdc2/3. Proteins found in basic chordates (Ciona) also distribute in these two subfamilies, whereas Popdc proteins of protostomes (Drosophila, Aplysia and Capitaella) form an independent subgroup equally distant from Popdc1 and Popdc2/3 subgroups. Significantly, however, the cnidarian (Clytia) Popdc protein appears to be orthologous to Popdc1, suggesting that Popdc1 represent the ancestral form of the protein family. (C) Protein sequence alignment of the PBC of Popdc proteins. Despite 650–850 million years of evolutionary distance between cnidarians and vertebrates, two sequence elements (FL/IDSPEW/F and FQVT/SL/I) are strongly conserved. (D) 3D model of the Popeye domain of human POPDC1. Similar to other cAMP-binding domains, the roof of the Popeye domain consists of a number β-strands, whereas the lid is α-helical and positions itself over the PBC in response to cyclic nucleotide binding and shields the ligand from solvent [36]. The residues of the PBC are depicted as yellow halos surrounding the cAMP molecule. The Cav3-binding site is also demarcated and located at the distal end of the lid domain. At this position, the binding site is likely to experience significant conformational changes in response to ligand binding. (E) Comparison of the consensus sequence of the PBC of Popdc proteins and the consensus sequence of cNMP-binding sites, which are aligned in PROSITE (http://prosite.expasy.org/PS00889). Note that the two consensus sequences do not resemble each other. In both cases, however, two stretches of conserved sequence motifs border a sequence of weak conservation. Amino acids labelled by a star in the Popdc sequence have been mutagenized and shown to be essential for cAMP binding [6].
Figure 3. Models of Popdc protein function(A) Switch model: Popdc protein might act as a switch that activates or inactivates proteins with which it forms a complex. The example depicted is the potassium channel TREK-1, which forms a complex with Popdc protein. Binding of cAMP may induce a change in protein conformation, leading to a modulation of the open probability of the associated ion channel. (B) Cargo model: Popdc proteins are found in cytoplasmic vesicles and may regulate the transport of effector proteins to the plasma membrane, which may also involve Cav3, with which Popdc proteins form a complex. Both models are supported by protein–protein interaction data of Popdc proteins with TREK-1 and Cav3 [6,35].
Alcalay,
Popeye domain containing 1 (Popdc1/Bves) is a caveolae-associated protein involved in ischemia tolerance.
2013, Pubmed
Alcalay,
Popeye domain containing 1 (Popdc1/Bves) is a caveolae-associated protein involved in ischemia tolerance.
2013,
Pubmed
Andrée,
Isolation and characterization of the novel popeye gene family expressed in skeletal muscle and heart.
2000,
Pubmed
Andrée,
Mouse Pop1 is required for muscle regeneration in adult skeletal muscle.
2002,
Pubmed
Benesh,
Bves and NDRG4 regulate directional epicardial cell migration through autocrine extracellular matrix deposition.
2013,
Pubmed
Brand,
The Popeye domain-containing gene family.
2005,
Pubmed
Breher,
Popeye domain containing gene 2 (Popdc2) is a myocyte-specific differentiation marker during chick heart development.
2004,
Pubmed
Charpentier,
Mouse models of SCN5A-related cardiac arrhythmias.
2008,
Pubmed
Davidson,
Evolutionary origins of the vertebrate heart: Specification of the cardiac lineage in Ciona intestinalis.
2003,
Pubmed
Davidson,
A morphological and genetic characterization of metamorphosis in the ascidian Boltenia villosa.
2003,
Pubmed
Enyedi,
Molecular background of leak K+ currents: two-pore domain potassium channels.
2010,
Pubmed
Froese,
Expression pattern of Popdc2 during mouse embryogenesis and in the adult.
2008,
Pubmed
Froese,
Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice.
2012,
Pubmed
Gazzerro,
Caveolinopathies: translational implications of caveolin-3 in skeletal and cardiac muscle disorders.
2011,
Pubmed
Gingold-Belfer,
Popeye domain-containing 1 is down-regulated in failing human hearts.
2011,
Pubmed
Hager,
Bves: ten years after.
2009,
Pubmed
Hager,
Identification of a novel Bves function: regulation of vesicular transport.
2010,
Pubmed
,
Xenbase
Hagiwara,
Immunolocalization of caveolin-1 and caveolin-3 in monkey skeletal, cardiac and uterine smooth muscles.
2002,
Pubmed
Harvey,
Caveolae create local signalling domains through their distinct protein content, lipid profile and morphology.
2012,
Pubmed
Heurteaux,
Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype.
2006,
Pubmed
Honoré,
The neuronal background K2P channels: focus on TREK1.
2007,
Pubmed
Hund,
Ankyrin-based targeting pathway regulates human sinoatrial node automaticity.
2008,
Pubmed
Kawaguchi,
Identification of a novel intracellular interaction domain essential for Bves function.
2008,
Pubmed
Kim,
Frequent silencing of popeye domain-containing genes, BVES and POPDC3, is associated with promoter hypermethylation in gastric cancer.
2010,
Pubmed
Kirchmaier,
The Popeye domain containing 2 (popdc2) gene in zebrafish is required for heart and skeletal muscle development.
2012,
Pubmed
Knight,
Membrane topology of Bves/Pop1A, a cell adhesion molecule that displays dynamic changes in cellular distribution during development.
2003,
Pubmed
McGrath,
Transcriptional analysis of the mammalian heart with special reference to its endocrine function.
2009,
Pubmed
Niu,
Dynamic properties of stretch-activated K+ channels in adult rat atrial myocytes.
2003,
Pubmed
Opthof,
The mammalian sinoatrial node.
1988,
Pubmed
Osler,
Bves modulates epithelial integrity through an interaction at the tight junction.
2005,
Pubmed
Razani,
Caveolae: from cell biology to animal physiology.
2002,
Pubmed
Reese,
bves: A novel gene expressed during coronary blood vessel development.
1999,
Pubmed
Rehmann,
Capturing cyclic nucleotides in action: snapshots from crystallographic studies.
2007,
Pubmed
Rodriguez,
Update on sick sinus syndrome, a cardiac disorder of aging.
1990,
Pubmed
Russ,
Inhibition of RhoA signaling with increased Bves in trabecular meshwork cells.
2010,
Pubmed
Simons,
Functional rafts in cell membranes.
1997,
Pubmed
Smith,
Bves directly interacts with GEFT, and controls cell shape and movement through regulation of Rac1/Cdc42 activity.
2008,
Pubmed
Tan,
Trek-like potassium channels in rat cardiac ventricular myocytes are activated by intracellular ATP.
2002,
Pubmed
Terrenoire,
A TREK-1-like potassium channel in atrial cells inhibited by beta-adrenergic stimulation and activated by volatile anesthetics.
2001,
Pubmed
Torlopp,
Comparative analysis of mRNA and protein expression of Popdc1 (Bves) during early development in the chick embryo.
2006,
Pubmed
Vasavada,
Developmental expression of Pop1/Bves.
2004,
Pubmed
Williams,
BVES regulates EMT in human corneal and colon cancer cells and is silenced via promoter methylation in human colorectal carcinoma.
2011,
Pubmed
Xian Tao Li,
The stretch-activated potassium channel TREK-1 in rat cardiac ventricular muscle.
2006,
Pubmed