Dwight W Martin | PubMed Health

PubMed2005

A transgenic mouse model of heart failure using inducible Galpha q.

Receptors coupled to Galpha q play a key role in the development of heart failure. Studies using genetically modified mice suggest that Galpha q mediates a hypertrophic response in cardiac myocytes. Galpha q signaling in these models is modified during early growth and development, whereas most heart failure in humans occurs after cardiac damage sustained during adulthood. To determine the phenotype of animals that express increased Galpha q signaling only as adults, we generated transgenic mice that express a silent Galpha q protein (Galpha qQ209L-hbER) in cardiac myocytes that can be activated by tamoxifen. Following drug treatment to activate Galpha q Q209L-hbER, these mice rapidly develop a dilated cardiomyopathy and heart failure. This phenotype does not appear to involve myocyte hypertrophy but is associated with dephosphorylation of phospholamban (PLB), decreased sarcoplasmic reticulum Ca2+-ATPase activity, and a decrease in L-type Ca2+ current density. Changes in Ca2+ handling and decreased cardiac contractility are apparent 1 week after Galpha qQ209L-hbER activation. In contrast, transgenic mice that express an inducible Galpha q mutant that cannot activate phospholipase Cbeta (PLCbeta) do not develop heart failure or changes in PLB phosphorylation, but do show decreased L-type Ca2+ current density. These results demonstrate that activation of Galpha q in cardiac myocytes of adult mice causes a dilated cardiomyopathy that requires the activation of PLCbeta. However, increased PLCbeta signaling is not required for all of the Galpha q-induced cardiac abnormalities.

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PubMed2005

Structure-function relationships in the NA+,K+-pump.

The Na,K-pump was discovered about 50 years ago. Since then there has been a methodic investigation of its structure and functional characteristics. The development of the Albers-Post model for the transport cycle was a milestone that provided the framework for detailed understanding of the transport process. The pump is composed of 2 subunits that exist in the membrane as an alphabeta heterodimer. All known enzymatic functions of the pump occur through the alpha subunit. Although necessary for activity, the complete role of the beta subunit is not understood fully. Numerous studies have established that the alphabeta protomer is the minimal functional unit needed to perform the Albers-Post reaction cycle. However, higher orders of aggregation [(alphabeta)n] are commonly detected. There is little evidence that oligomerization has functional consequence for ion transport. The Na+,K+-adenosine triphosphatase (ATPase) is a member of the P-type ATPase family of transporters. Proteins within this family have common amino acid sequence motifs that share functional characteristics and structure. Low-resolution 3-dimensional reconstruction of 2-dimensional crystal diffractions provide evidence for the similarity in tertiary structure of the alpha subunit and the Ca2+ATPase (a closely related P-type ATPase). The spatial location of the beta subunit also is obvious in these reconstructions. Recent high-resolution reconstructions from 3-dimensional crystals of the Ca2+ATPase provide structural details at the atomic level. It now is possible to interpret structurally some of the key steps in the Albers-Post reaction. Some of these high-resolution interpretations are translatable to the Na+,K+-ATPase, but a high-resolution structure of the Na,K-pump is needed for the necessary details of those aspects that are unique to this transporter.

Animals↗