Disease relevance of Trdn

• HRC knockout mice exhibited impaired weight gain beginning at 11 months of age, which was marked by reduced skeletal muscle and fat mass, and triadin protein expression was upregulated in the heart of HRC knockout mice [1].
• Cardiac hypertrophy and impaired relaxation in transgenic mice overexpressing triadin 1 [2].

High impact information on Trdn

• Interestingly, the proteins involved in the Ca2+-release cascade (ryanodine receptor, junctin, and triadin) were downregulated, whereas Ca2+-uptake proteins (Ca2+-ATPase and phospholamban) were unchanged or slightly increased [3].
• These cells, upon withdrawal of mitogens for 5-7 d, were shown by Western blot analysis to express key triadic proteins, including skeletal triadin, calsequestrin, FK506-binding protein, 12 kD, sarco(endo)plasmic reticulum calcium-ATPase1, and dihydropyridine receptors [4].
• Immunofluorescence labelings of differentiating myocytes with antibodies against alpha1 and alpha2 subunits of DHPRs, RyRs, and triadin show that the skeletal isoforms of all four proteins are abundantly expressed upon differentiation, they appear concomitantly, and they are colocalized [5].
• In addition, HRCBP interacts with triadin, a protein associated with the ryanodine receptor and thought to be involved in calcium release [1].
• To better understand the role of triadin 1 in excitation-contraction coupling in the heart, we generated transgenic mice with targeted overexpression of triadin 1 to mouse atrium and ventricle, employing the alpha-myosin heavy chain promoter to drive protein expression [2].

Biological context of Trdn

• Hence, triadin 1 overexpression triggered time-dependent alterations in SR protein expression, Ca(2+) homeostasis, and contractility, indicating for the first time an inhibitory function of triadin 1 on SR-Ca(2+) release in vivo [6].
• We conclude that in 3-wk-old atria, junctin overexpression was associated with a reduced expression of triadin 1 resulting in a higher SR Ca2+ load without changes in contractility or heart rate [7].
• Overexpression of junctin led to down-regulation of triadin and RyR but to up-regulation of dihydropyridine receptor [8].

Anatomical context of Trdn

• Although a 92-kDa immunoreactive protein could be tentatively identified in myocardium as triadin 3, its expression level was insignificant (</=5%) compared with that of triadin 1 [9].
• All antibodies detected two prominent proteins of molecular masses 35 and 40 kDa on immunoblots from cardiac microsomes, including the antibody that recognizes only triadin 1 [9].
• Cardiac myocytes from triadin 1-overexpressing mice exhibited depressed contractility; Ca(2+) transients decayed at a slower rate, and cell shortening and relengthening were diminished [2].
• The junctions show coupling between exterior membranes and SR, and an apparently normal content and disposition of triadin and calsequestrin [10].
• In normal differentiating muscle fibers DHPRs, triadin and RyRs are located in intensely immunolabeled foci that are randomly distributed across the fiber [11].

Associations of Trdn with chemical compounds

• We conclude that triadin 1 is the triadin isoform most likely to play a role in Ca(2+) release in heart [9].
• The glycosylation site of triadin 1 was localized to asparagine residue 75, and its bitopic arrangement in the membrane was confirmed [9].
• RESULTS: The overexpression of triadin 1 was associated with an enhanced SR Ca2+ load, reflected by a 22% higher amplitude of caffeine-induced Ca2+ transients [12].
• Triadin in the high salt hydroxylapatite extract could also be immunoprecipitated by a monoclonal antibody to the junctional foot protein [13].
• Purified reduced triadin is not retained on a hydroxylapatite column in the presence of 30 mM Potassium phosphate, while the junctional foot protein and dihydropyridine receptor purified in the absence of triadin are both retained [13].

Physical interactions of Trdn

• Localization and characterization of the calsequestrin-binding domain of triadin 1. Evidence for a charged beta-strand in mediating the protein-protein interaction [14].
• Collectively, these results demonstrate a role for triadin as the linkage between the junctional foot protein and dihydropyridine receptor creating a ternary complex at the triad junction in skeletal muscle [13].

Regulatory relationships of Trdn

• To better understand the role of triadin 1 in SR-Ca(2+) release, we studied the time-dependent expression of SR proteins and contractility in atria of 3-, 6-, and 18-wk-old transgenic mice overexpressing canine cardiac triadin 1 under control of the alpha-myosin heavy chain (MHC) promoter [6].

Other interactions of Trdn

• Its calcium binding properties, localization to the SR, and interaction with triadin suggest that HRCBP is involved in calcium handling by the SR [1].
• Confirming this, overexpression of triadin 1 in transgenic mouse hearts produced both the 35-kDa deglycosylated and the 40-kDa glycosylated mobility forms [9].
• Moreover, triadin 1 appears to anchor calsequestrin to the ryanodine receptor [12].
• The SR Ca-ATPase has more diffuse distribution than triadin in both normal and dyspedic fibers [11].

Analytical, diagnostic and therapeutic context of Trdn

• Using immunohistochemistry and freeze-fracture electron microscopy, we find that DHPR and triadin are clustered in foci in differentiating 1B5 cells [15].
• Triadin and the dihydropyridine receptor were, however, separated from the junctional foot protein on rate zonal centrifugation [13].

References