Lactate Elicits ER-Mitochondrial Mg Dynamics to Integrate Cellular Metabolism.

Mg is the most abundant divalent cation in metazoans and an essential cofactor for ATP, nucleic acids, and countless metabolic enzymes. To understand how the spatio-temporal dynamics of intracellular Mg (Mg) are integrated into cellular signaling, we implemented a comprehensive screen to discover regulators of Mg dynamics. Lactate emerged as an activator of rapid release of Mg from endoplasmic reticulum (ER) stores, which facilitates mitochondrial Mg (Mg) uptake in multiple cell types.

Phosphatidylinositol 4,5-bisphosphate directly interacts with the β and γ subunits of the sodium channel ENaC.

The plasma membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP) regulates the activity of diverse ion channels to include the epithelial Na channel ENaC. Whether PIP regulation of ENaC is due to a direct phospholipid-protein interaction, remains obscure. To date, possible interaction of PIP with ENaC primarily has been tested indirectly through assays of channel function.

Mitochondrial pyruvate and fatty acid flux modulate MICU1-dependent control of MCU activity.

The tricarboxylic acid (TCA) cycle converts the end products of glycolysis and fatty acid β-oxidation into the reducing equivalents NADH and FADH Although mitochondrial matrix uptake of Ca enhances ATP production, it remains unclear whether deprivation of mitochondrial TCA substrates alters mitochondrial Ca flux. We investigated the effect of TCA cycle substrates on MCU-mediated mitochondrial matrix uptake of Ca, mitochondrial bioenergetics, and autophagic flux. Inhibition of glycolysis, mitochondrial pyruvate transport, or mitochondrial fatty acid transport triggered expression of the MCU gatekeeper MICU1 but not the MCU core subunit.

Liddle's syndrome mechanisms, diagnosis and management.

Liddle's syndrome is a genetic disorder characterized by hypertension with hypokalemic metabolic alkalosis, hyporeninemia and suppressed aldosterone secretion that often appears early in life. It results from inappropriately elevated sodium reabsorption in the distal nephron. Liddle's syndrome is caused by mutations to subunits of the Epithelial Sodium Channel (ENaC).

Fluorescence spectral shape analysis for nucleotide identification.

We report a conjugated polyelectrolyte fluorescence-based biosensor P-C-3 and a general methodology to evaluate spectral shape recognition to identify biomolecules using artificial intelligence. By using well-defined analytes, we demonstrate that the fluorescence spectral shape of P-C-3 is sensitive to minor structural changes and exhibits distinct signature patterns for different analytes. A method was also developed to select useful features to reduce computational complexity and prevent overfitting of the data.

A mutually induced conformational fit underlies Ca-directed interactions between calmodulin and the proximal C terminus of KCNQ4 K channels.

Calmodulin (CaM) conveys intracellular Ca signals to KCNQ (Kv7, "M-type") K channels and many other ion channels. Whether this "calmodulation" involves a dramatic structural rearrangement or only slight perturbations of the CaM/KCNQ complex is as yet unclear. A consensus structural model of conformational shifts occurring between low nanomolar and physiologically high intracellular [Ca] is still under debate.