Myocyte-enriched calcineurin-interacting protein, MCIP1, inhibits cardiac hypertrophy in vivo

Signaling events controlled by calcineurin promote cardiac hypertrophy, but the degree to which such pathways are required to transduce the effects of various hypertrophic stimuli remains uncertain. In particular, the administration of immunosuppressive drugs that inhibit calcineurin has inconsistent effects in blocking cardiac hypertrophy in various animal models. As an alternative approach to inhibiting calcineurin in the hearts of intact animals, transgenic mice were engineered to overexpress a human cDNA encoding the calcineurin-binding protein, myocyte-enriched calcineurin-interacting protein-1 (hMCIP1) under control of the cardiac-specific, α-myosin heavy chain promoter (α-MHC). In unstressed mice, forced expression of hMCIP1 resulted in a 5–10% decline in cardiac mass relative to wild-type littermates, but otherwise produced no apparent structural or functional abnormalities. However, cardiac-specific expression of hMCIP1 inhibited cardiac hypertrophy, reinduction of fetal gene expression, and progression to dilated cardiomyopathy that otherwise result from expression of a constitutively active form of calcineurin. Expression of the hMCIP1 transgene also inhibited hypertrophic responses to β-adrenergic receptor stimulation or exercise training. These results demonstrate that levels of hMCIP1 producing no apparent deleterious effects in cells of the normal heart are sufficient to inhibit several forms of cardiac hypertrophy, and suggest an important role for calcineurin signaling in diverse forms of cardiac hypertrophy. The future development of measures to increase expression or activity of MCIP proteins selectively within the heart may have clinical value for prevention of heart failure.

Tracking memory's trace

There is strong converging evidence that the intermediate and medial part of the hyperstriatum ventrale of the chick brain is a memory store for information acquired through the learning process of imprinting. Neurons in this memory system come, through imprinting, to respond selectively to the imprinting stimulus (IS) neurons and so possess the properties of a memory trace. Therefore, the responses of the intermediate and medial part of the hyperstriatum ventrale neurons to a visual imprinting stimulus were determined before, during, and after training. Of the total recorded population, the proportions of IS neurons shortly after each of two 1-h training sessions were significantly higher (approximately 2 times) than the pretraining proportion. However, ≈4.5 h later this proportion had fallen significantly and did not differ significantly from the pretraining proportion. Nevertheless, ≈21.5 h after the end of training, the proportion of IS neurons was at its highest (approximately 3 times the pretraining level). No significant fluctuations occurred in the proportions of neurons responding to the alternative stimulus. In addition, nonmonotonic changes were found commonly in the activity of 230 of the neurons tracked individually from before training to shortly after the end of training. Thus the pattern of change in responsiveness both at the population level and at the level of individual neurons was highly nonmonotonic. Such a pattern of change is not consistent with simple models of memory based on synaptic strengthening to asymptote. A model is proposed that accounts for the changes in the population responses to the imprinting stimulus in terms of changes in the responses of individual neurons.

The "DEAD box" protein DbpA interacts specifically with the peptidyltransferase center in 23S rRNA.

The Escherichia coli DEAD (Asp-Glu-Ala-Asp) box protein DbpA is a putative RNA helicase and established RNA-dependent ATPase and is the only member of the DEAD box protein family for which a specific RNA substrate, bacterial 23S rRNA, has been identified. We have investigated the nature of this specificity in depth and have localized by deletion mutagenesis and PCR a single region of 93 bases (bases 2496-2588) in 23S rRNA that is both necessary and sufficient for complete activation of ATPase activity of DbpA. This target region forms part of the peptidyltransferase center and includes many bases involved in interaction with the 3' terminal adenosines of both A- and P-site tRNAs. Deletion of stem loops within the 93-base segment abolished ATPase activation. Similarly, point mutations that disrupt base pairing within stem structures ablated stimulation of ATPase activity. These data are consistent with roles for DbpA either in establishing and/or maintaining the correct three-dimensional structure of the peptidyltransferase center in 23S rRNA during ribosome assembly or in the peptidyltransferase reaction.