Regulation of ecto-5'-nucleotidase activity via Ca2+-dependent, annexin 2-mediated membrane rearrangement?

The spatial segregation of the plasma membrane plays a prominent role in distinguishing and sorting a large number of signals a cell receives simultaneously. The plasma membrane comprises regions known as lipid rafts, which serve as signal-transduction hubs and platforms for sorting membrane-associated proteins. Ca(2+)-binding proteins of the annexin family have been ascribed a role in the regulation of raft dynamics. Glycosylphosphatidylinositol-anchored 5'-nucleotidase is an extracellular, raft-associated enzyme responsible for conversion of extracellular ATP into adenosine. Our results point to a regulation of ecto-5'-nucleotidase activity by Ca(2+)-dependent, annexin-mediated stabilization of membrane rafts.

A guide to sparkology: the taxonomy of elementary cellular Ca2+ signaling events

Since the discovery of the Ca(2+) spark as an elementary event of cellular Ca(2+) signaling almost 15 years ago, the family of newly described Ca(2+) signal entities has been ever growing. While scientists working in Ca(2+) signaling may have maintained an overview over the specifics of this nomenclature, those outside the field often make the complaint that they feel hopelessly lost. With the present review we collect and summarize systematic information on the many Ca(2+) signaling events described in a variety of tissues and cells, and we emphasize why and how each of them has its own importance. Most of these signals are taking place in the cytosol of the respective cells, but several events have been recorded from intracellular organelles as well, where they may serve their own specific functions. Finally, we also try to convey an integrated view as to why cellular microdomain signaling is of fundamental biological importance.

Increased expression of the auxiliary beta2-subunit of ventricular L-type Ca2+ channels leads to single-channel activity characteristic of heart failure

BACKGROUND: Increased activity of single ventricular L-type Ca(2+)-channels (L-VDCC) is a hallmark in human heart failure. Recent findings suggest differential modulation by several auxiliary beta-subunits as a possible explanation. METHODS AND RESULTS: By molecular and functional analyses of human and murine ventricles, we find that enhanced L-VDCC activity is accompanied by altered expression pattern of auxiliary L-VDCC beta-subunit gene products. In HEK293-cells we show differential modulation of single L-VDCC activity by coexpression of several human cardiac beta-subunits: Unlike beta(1) or beta(3) isoforms, beta(2a) and beta(2b) induce a high-activity channel behavior typical of failing myocytes. In accordance, beta(2)-subunit mRNA and protein are up-regulated in failing human myocardium. In a model of heart failure we find that mice overexpressing the human cardiac Ca(V)1.2 also reveal increased single-channel activity and sarcolemmal beta(2) expression when entering into the maladaptive stage of heart failure. Interestingly, these animals, when still young and non-failing ("Adaptive Phase"), reveal the opposite phenotype, viz: reduced single-channel activity accompanied by lowered beta(2) expression. Additional evidence for the cause-effect relationship between beta(2)-subunit expression and single L-VDCC activity is provided by newly engineered, double-transgenic mice bearing both constitutive Ca(V)1.2 and inducible beta(2) cardiac overexpression. Here in non-failing hearts induction of beta(2)-subunit overexpression mimicked the increase of single L-VDCC activity observed in murine and human chronic heart failure. CONCLUSIONS: Our study presents evidence of the pathobiochemical relevance of beta(2)-subunits for the electrophysiological phenotype of cardiac L-VDCC and thus provides an explanation for the single L-VDCC gating observed in human and murine heart failure.

On how high performers keep cool brains in situations of cognitive overload

What happens in the brain when we reach or exceed our capacity limits? Are there individual differences for performance at capacity limits? We used functional magnetic resonance imaging (fMRI) to investigate the impact of increases in processing demand on selected cortical areas when participants performed a parametrically varied and challenging dual task. Low-performing participants respond with large and load-dependent activation increases in many cortical areas when exposed to excessive task requirements, accompanied by decreasing performance. It seems that these participants recruit additional attentional and strategy-related resources with increasing difficulty, which are either not relevant or even detrimental to performance. In contrast, the brains of the high-performing participants "keep cool" in terms of activation changes, despite continuous correct performance, reflecting different and more efficient processing. These findings shed light on the differential implications of performance on activation patterns and underline the importance of the interindividual-differences approach in neuroimaging research.

Mechanisms and regulation of epithelial Ca2+ absorption in health and disease

Ca2+ is essential for numerous physiological functions in our bodies. Therefore, its homeostasis is finely maintained through the coordination of intestinal absorption, renal reabsorption, and bone resorption. The Ca2+-selective epithelial channels TRPV5 and TRPV6 have been identified, and their physiological roles have been revealed: TRPV5 is important in final renal Ca2+ reabsorption, and TRPV6 has a key role in intestinal Ca2+ absorption. The TRPV5 knockout mice exhibit renal leak hypercalciuria and accordingly upregulate their intestinal TRPV6 expression to compensate for their negative Ca2+ balance. In contrast, despite their severe negative Ca2+ balance, TRPV6-null mice do not display any compensatory mechanism, thus resulting in secondary hyperparathyroidism. These results indicate that the genes for TRPV5 and TRPV6 are differentially regulated in human diseases associated with disturbed Ca2+ balance such as hypercalciuria, osteoporosis, and vitamin D-resistant rickets.