Ryanodine receptors are part of the myospryn complex in cardiac muscle

The Cardiomyopathy–associated gene 5 (Cmya5) encodes myospryn, a large tripartite motif (TRIM)-related protein found predominantly in cardiac and skeletal muscle. Cmya5 is an expression biomarker for a number of diseases affecting striated muscle and may also be a schizophrenia risk gene. To further understand the function of myospryn in striated muscle, we searched for additional myospryn paralogs. Here we identify a novel muscle-expressed TRIM-related protein minispryn, encoded by Fsd2, that has extensive sequence similarity with the C-terminus of myospryn. Cmya5 and Fsd2 appear to have originated by a chromosomal duplication and are found within evolutionarily-conserved gene clusters on different chromosomes. Using immunoaffinity purification and mass spectrometry we show that minispryn co-purifies with myospryn and the major cardiac ryanodine receptor (RyR2) from heart. Accordingly, myospryn, minispryn and RyR2 co-localise at the junctional sarcoplasmic reticulum of isolated cardiomyocytes. Myospryn redistributes RyR2 into clusters when co-expressed in heterologous cells whereas minispryn lacks this activity. Together these data suggest a novel role for the myospryn complex in the assembly of ryanodine receptor clusters in striated muscle

Non-genomic effect of testosterone on airway smooth muscle

Background and purpose: Recent studies on blood vessels have provided evidence that testosterone may exert direct effects on smooth muscle. However, an acute effect on airway reactivity has not been shown yet. The aim of this study was to assess the direct effect of testosterone on the responsiveness of male adult rabbit airway smooth muscle (ASM), precontracted with 10 mu M acetylcholine, 10 mu M carbachol or 80 mM KCl. Experimental approach: Contractility studies of rabbit tracheal smooth muscle were performed. Key results: Testosterone at concentrations of or above 1 nM had a significant relaxant effect on ASM precontracted with acetylcholine or carbachol, but did not affect ASM precontracted with KCl. The mechanical removal of airway epithelium as well as the inhibition of NO synthetase (by 100 mu M L-NAME) reduced the relaxation caused by testosterone. The effect of testosterone was not altered by impairing prostanoid synthesis (by 10mM indomethacin). The nitric oxide donor, sodium nitroprusside, had the same relaxant effect on ASM precontracted with either carbachol or KCl. Inhibitors of androgen receptors (10mM flutamide) or DNA transcription (100mM actinomycin D) did not alter the effect of testosterone. Prolonged incubation of ASM with 100 nM or 100 mM testosterone for 24 or 48 h did not alter their responsiveness to acetylcholine. BSAtestosterone (1pM to 100nM) relaxed significantly ASM precontracted with carbachol. The mechanical removal of airway epithelium abolished the relaxant effect of BSA-testosterone. Conclusions and implications: Testosterone relaxes precontracted ASM via an epithelium and NO-mediated way. This effect is mediated via a non-genomic pathway

Deregulated Protein Kinase A Signaling and Myospryn Expression in Muscular Dystrophy*S⃞

Alterations in signaling pathway activity have been implicated in the pathogenesis of Duchenne muscular dystrophy, a degenerative muscle disease caused by a deficiency in the costameric protein dystrophin. Accordingly, the notion of the dystrophin-glycoprotein complex, and by extension the costamere, as harboring signaling components has received increased attention in recent years. The localization of most, if not all, signaling enzymes to this subcellular region relies on interactions with scaffolding proteins directly or indirectly associated with the dystrophin-glycoprotein complex. One of these scaffolds is myospryn, a large, muscle-specific protein kinase A (PKA) anchoring protein or AKAP. Previous studies have demonstrated a dysregulation of myospryn expression in human Duchenne muscular dystrophy, suggesting a connection to the pathophysiology of the disorder. Here we report that dystrophic muscle exhibits reduced PKA activity resulting, in part, from severely mislocalized myospryn and the type II regulatory subunit (RIIα) of PKA. Furthermore, we show that myospryn and dystrophin coimmunoprecipitate in native muscle extracts and directly interact in vitro. Our findings reveal for the first time abnormalities in the PKA signal transduction pathway and myospryn regulation in dystrophin deficiency

GWA study data mining and independent replication identify cardiomyopathy-associated 5 (CMYA5) as a risk gene for schizophrenia.

We conducted data-mining analyses using the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and molecular genetics of schizophrenia genome-wide association study supported by the genetic association information network (MGS-GAIN) schizophrenia data sets and performed bioinformatic prioritization for all the markers with P-values less than or equal to0.05 in both data sets. In this process, we found that in the CMYA5 gene, there were two non-synonymous markers, rs3828611 and rs10043986, showing nominal significance in both the CATIE and MGS-GAIN samples. In a combined analysis of both the CATIE and MGS-GAIN samples, rs4704591 was identified as the most significant marker in the gene. Linkage disequilibrium analyses indicated that these markers were in low LD (3 828 611–rs10043986, r2=0.008; rs10043986–rs4704591, r2=0.204). In addition, CMYA5 was reported to be physically interacting with the DTNBP1 gene, a promising candidate for schizophrenia, suggesting that CMYA5 may be involved in the same biological pathway and process. On the basis of this information, we performed replication studies for these three single-nucleotide polymorphisms. The rs3828611 was found to have conflicting results in our Irish samples and was dropped out without further investigation. The other two markers were verified in 23 other independent data sets. In a meta-analysis of all 23 replication samples (family samples, 912 families with 4160 subjects; case–control samples, 11 380 cases and 15 021 controls), we found that both markers are significantly associated with schizophrenia (rs10043986, odds ratio (OR)=1.11, 95% confidence interval (CI)=1.04–1.18, P=8.2 × 10−4 and rs4704591, OR=1.07, 95% CI=1.03–1.11, P=3.0 × 10−4). The results were also significant for the 22 Caucasian replication samples (rs10043986, OR=1.11, 95% CI=1.03–1.17, P=0.0026 and rs4704591, OR=1.07, 95% CI=1.02–1.11, P=0.0015). Furthermore, haplotype conditioned analyses indicated that the association signals observed at these two markers are independent. On the basis of these results, we concluded that CMYA5 is associated with schizophrenia and further investigation of the gene is warranted