Disease relevance of Asph

• Overexpression of the junctin in mouse heart was associated with heart enlargements, bradycardia, atrial fibrillation, and increased fibrosis [1].
• The ratio of atrial weight and body weight was unchanged between junctin-overexpressing (JCN) and wild-type (WT) mice at all ages investigated (n=6-8) [2].
• Ablation of junctin is associated with aberrant Ca homeostasis, which leads to fatal arrhythmias [3].
• Long-term isoproterenol infusion also induced premature ventricular contractions and atrioventricular heart block in junctin-null mice [3].

High impact information on Asph

• Aspartyl beta-hydroxylase: in vitro hydroxylation of a synthetic peptide based on the structure of the first growth factor-like domain of human factor IX [4].
• Aspartyl beta-hydroxylase appears to require the same cofactors as known alpha-ketoglutarate-dependent dioxygenases [4].
• BAH null mice lack measurable BAH protein in several tissues, lack aspartyl beta-hydroxylase activity in liver preparations, and exhibit no hydroxylation of the epidermal growth factor (EGF) domain of clotting Factor X [5].
• To evaluate the role of BAH in vivo, the catalytic domain of BAH was specifically targeted such that the coding regions of junctin and humbug remained undisturbed [5].
• Because the 26-kDa calsequestrin binding protein is an integral component of the junctional sarcoplasmic reticulum membrane in cardiac and skeletal muscle, we have named it Junctin [6].

Biological context of Asph

• We show that junctate binds to TRPC2 independently of the calcium concentration and that the junctate binding site does not overlap with the common IP3R/calmodulin binding sites [7].
• Screening a mouse heart cDNA library using canine junctin cDNA as a probe yielded three complete mouse heart cDNAs [8].
• Junctate is a newly identified integral ER/SR membrane calcium binding protein, which is an alternative splicing form of the same gene generating aspartyl beta-hydroxylase and junctin [8].
• Overexpression of junctin led to down-regulation of triadin and RyR but to up-regulation of dihydropyridine receptor [1].
• CONCLUSION: Our data provide evidence that cardiac-specific overexpression of junctin is accompanied by impaired myocardial relaxation with prolonged Ca(2+) transient kinetics on the cardiomyocyte level [9].

Anatomical context of Asph

• Junctin and calsequestrin overexpression in cardiac muscle: the role of junctin and the synthetic and delivery pathways for the two proteins [10].
• Overexpression of junctin causes adaptive changes in cardiac myocyte Ca(2+) signaling [11].
• Junctin is a 26-kDa integral membrane protein, colocalized with the ryanodine receptor (RyR) and calsequestrin at the junctional sarcoplasmic reticulum (SR) membrane in cardiac and skeletal muscles [1].
• Significant homologies were found with triadin and aspartyl beta-hydroxylase, suggesting that all three proteins are members of a family of single membrane-spanning endoplasmic reticulum proteins [6].
• Isolated electrically stimulated papillary muscles from junctin-overexpressing hearts exhibited prolonged mechanical relaxation, and echocardiographic parameters of relaxation were prolonged in the living transgenic mice [9].

Associations of Asph with chemical compounds

• The amplitude of caffeine-induced Ca(2+) transients was lower in cardiomyocytes from junctin-overexpressing mice [9].
• The inactivation kinetics of L-type Ca(2+) channel were prolonged in junctin-overexpressing cardiomyocytes using Ca(2+) or Ba(2+) as charge carriers [9].

Other interactions of Asph

• This critical region contains two known genes (Asph and Gfd6) and three predicted genes, all of which are positional candidates for Tcm [12].
• Cardiac remodeling and atrial fibrillation in transgenic mice overexpressing junctin [1].
• Junctate, an inositol 1,4,5-triphosphate receptor associated protein, is present in rodent sperm and binds TRPC2 and TRPC5 but not TRPC1 channels [7].
• Altogether, these results provide a new hypothesis concerning sperm TRPC2 gating: TRPC2 activation may be due to modifications of its interaction with both junctate and IP3R, induced by depletion of calcium from the acrosomal vesicle [7].
• Triadin 1 overexpression was accompanied by time-dependent changes in the protein expression of the ryanodine receptor, junctin, and cardiac/slow-twitch muscle SR Ca(2+)-ATPase isoform [13].

Analytical, diagnostic and therapeutic context of Asph

• Molecular cloning and characterization of mouse cardiac junctate isoforms [8].
• To probe the contribution of junctin to the architecture of calcium release units in heart, we engineered transgenic mice overexpressing canine junctin and examined the left ventricular myocardium by electron microscopy [14].

References