Popeye Domain Containing 1 (Popdc1/Bves) Is a Caveolae-Associated Protein Involved in Ischemia Tolerance

Abstract

Popeye domain containing1 (Popdc1), also named Bves, is an evolutionary conserved membrane protein. Despite its high expression level in the heart little is known about its membrane localization and cardiac functions. The study examined the hypothesis that Popdc1 might be associated with the caveolae and play a role in myocardial ischemia tolerance. To address these issues, we analyzed hearts and cardiomyocytes of wild type and Popdc1-null mice. Immunoconfocal microscopy revealed co-localization of Popdc1 with caveolin3 in the sarcolemma, intercalated discs and T-tubules and with costameric vinculin. Popdc1 was co-immunoprecipitated with caveolin3 from cardiomyocytes and from transfected COS7 cells and was co-sedimented with caveolin3 in equilibrium density gradients. Caveolae disruption by methyl-β-cyclodextrin or by ischemia/reperfusion (I/R) abolished the cellular co-localization of Popdc1 with caveolin3 and modified their density co-sedimentation. The caveolin3-rich fractions of Popdc1-null hearts redistributed to fractions of lower buoyant density. Electron microscopy showed a statistically significant 70% reduction in caveolae number and a 12% increase in the average diameter of the remaining caveolae in the mutant hearts. In accordance with these changes, Popdc1-null cardiomyocytes displayed impaired [Ca+2]i transients, increased vulnerability to oxidative stress and no pharmacologic preconditioning. In addition, induction of I/R injury to Langendorff-perfused hearts indicated a significantly lower functional recovery in the mutant compared with wild type hearts while their infarct size was larger. No improvement in functional recovery was observed in Popdc1-null hearts following ischemic preconditioning. The results indicate that Popdc1 is a caveolae-associated protein important for the preservation of caveolae structural and functional integrity and for heart protection.

POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking

“…We studied the expression of proteins involved in membrane stability and repair in PTI-1 and PTIII-2 in comparison with 2 controls (Supplemental Figures 5-9). We previously reported protein-protein interaction of POPDC1 with CAV3 (12). However, the membrane presence of CAV3 was not altered in the patients' POPDC2 were prominently expressed in the sarcolemma ( Figure 2, A, B, E, and Figure 3, A, B, and E).…”

“…The Popdc1 null mutant in mice displays a retardation of muscle regeneration (13). Moreover, an impaired recovery from cardiac ischemia and an increase in infarct size have been described in the Popdc1 null mutant (12). Both Popdc1 and Popdc2 null mutants display a stress-induced sinus node bradycardia, which develops in an age-dependent manner (10,14).…”

“…POPDC proteins are localized primarily at the plasma membrane and in t-tubules (10), although they have also been found at the nuclear envelope of striated muscle cells (11). An interaction of POPDC proteins with CAV3 and the 2-pore domain potassium channel TREK-1 has been reported (10,12). In the presence of POPDC proteins, TREK-1 cur-…”

BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis

“…More recently, it was reported that BVES plays a regulatory role in cardiac pacemaking through binding of cAMP and interacting with potassium channel TREK-1 41 . Further, BVES interacts with CAV3, a caveolin expressed in the muscle tissue, and cardiac myocytes in Bves −/− mice have altered calveolar number and size 42 . Thus, BVES, through scaffolding with protein complexes, regulates a wide variety of basic, yet essential, cellular processes.…”

Popdc1/Bves Functions in the Preservation of Cardiomyocyte Viability While Affecting Rac1 Activity and Bnip3 Expression

“…In the human heart, Popdc1/Bves is markedly reduced during end stage heart failure and mutated Popdc1/Bves has been identified in patients born with Fallot's tetralogy and with muscular dystrophy [Gingold‐Belfer et al, ; Wu et al, ; Schindler et al, ], suggesting its involvement in heart pathology and morphogenesis. The ability of Popdc1/Bves to interact with ion channels and bind cAMP [Froese et al, ], as well as the presence of Popdc1/Bves in the caveolae and its interaction with caveolin3 [Alcalay et al, ], provide a partial description of mechanisms underlying the functional deficits reported in hearts lacking Popdc1/Bves. In addition, the downregulation of Popdc1/Bves expression due to promoter hypermethylation has been associated with tumorigenic transformation in humans that correlated with increased cell motility and invasiveness [Kim et al, ; Williams et al, ; Han et al, ].…”