Disruption of Phosphodiesterase 3A Binding to SERCA2 Increases SERCA2 Activity and Reduces Mortality in Mice With Chronic Heart Failure.

Background: Increasing SERCA2 (sarco[endo]-plasmic reticulum Ca ATPase 2) activity is suggested to be beneficial in chronic heart failure, but no selective SERCA2-activating drugs are available. PDE3A (phosphodiesterase 3A) is proposed to be present in the SERCA2 interactome and limit SERCA2 activity. Disruption of PDE3A from SERCA2 might thus be a strategy to develop SERCA2 activators.

Targeting protein-protein interactions in complexes organized by A kinase anchoring proteins.

Cyclic AMP is a ubiquitous intracellular second messenger involved in the regulation of a wide variety of cellular processes, a majority of which act through the cAMP - protein kinase A (PKA) signaling pathway and involve PKA phosphorylation of specific substrates. PKA phosphorylation events are typically spatially restricted and temporally well controlled. A-kinase anchoring proteins (AKAPs) directly bind PKA and recruit it to specific subcellular loci targeting the kinase activity toward particular substrates, and thereby provide discrete spatiotemporal control of downstream phosphorylation events.

Hyperpolarization-activated cyclic nucleotide-gated channels and cAMP-dependent modulation of exocytosis in cultured rat lactotrophs.

Hormone and neurotransmitter release from vesicles is mediated by regulated exocytosis, where an aqueous channel-like structure, termed a fusion pore, is formed. It was recently shown that second messenger cAMP modulates the fusion pore, but the detailed mechanisms remain elusive. In this study, we asked whether the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are activated by cAMP, are involved in the regulation of unitary exocytic events.

Differences in the expression pattern of HCN isoforms among mammalian tissues: sources and implications.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a critical role in a broad range of cell types, but the expression of the various HCN isoforms is still poorly understood. In the present study we have compared the expression of HCN isoforms in rat excitable and non-excitable tissues at both the mRNA and protein levels. Real-time PCR and Western blot analysis revealed distinct expression patterns of the four HCN isoforms in brain, heart, pituitary and kidney, with inconsistent mRNA-protein expression correlation.

Vesicle size determines unitary exocytic properties and their sensitivity to sphingosine.

Neuroendocrine cells contain small and large vesicles, but the functional significance of vesicle diameter is unclear. We studied unitary exocytic events of prolactin-containing vesicles in lactotrophs by monitoring discrete steps in membrane capacitance. In the presence of sphingosine, which recruits VAMP2 for SNARE complex formation, the frequency of transient and full fusion events increased.

cAMP-mediated stabilization of fusion pores in cultured rat pituitary lactotrophs.

Regulated exocytosis mediates the release of hormones and transmitters. The last step of this process is represented by the merger between the vesicle and the plasma membranes, and the formation of a fusion pore. Once formed, the initially stable and narrow fusion pore may reversibly widen (transient exocytosis) or fully open (full-fusion exocytosis).

Comparison of unitary exocytic events in pituitary lactotrophs and in astrocytes: modeling the discrete open fusion-pore states.

In regulated exocytosis the merger between the vesicle and the plasma membranes leads to the formation of an aqueous channel (a fusion-pore), through which vesicular secretions exit into the extracellular space. A fusion pore was thought to be a short-lived intermediate preceding full-fusion of the vesicle and the plasma membranes (full-fusion exocytosis). However, transient exocytic events were also observed, where the fusion-pore opens and closes, repetitively.

Fusion pore diameter regulation by cations modulating local membrane anisotropy.

The fusion pore is an aqueous channel that is formed upon the fusion of the vesicle membrane with the plasma membrane. Once the pore is open, it may close again (transient fusion) or widen completely (full fusion) to permit vesicle cargo discharge. While repetitive transient fusion pore openings of the vesicle with the plasma membrane have been observed in the absence of stimulation, their frequency can be further increased using a cAMP-increasing agent that drives the opening of nonspecific cation channels.

Life and death in aluminium-exposed cultures of rat lactotrophs studied by flow cytometry.

Prolonged exposure to aluminium may impact health. Aluminium's deleterious effects are mostly attributed to its selective accumulation in particular organs and cell types. Occupational exposure to aluminium is allied with a reduced level of serum prolactin, a stress peptide hormone mainly synthesised and secreted by the anterior pituitary lactotrophs.

Comparative effects of aluminum and ouabain on synaptosomal choline uptake, acetylcholine release and (Na+/K+)ATPase.

Closing the gap between adverse health effects of aluminum and its mechanisms of action still represents a huge challenge. Cholinergic dysfunction has been implicated in neuronal injury induced by aluminum. Previously reported data also indicate that in vivo and in vitro exposure to aluminum inhibits the mammalian (Na(+)/K(+))ATPase, an ubiquitous plasma membrane pump.