Novel Anticancer Strategy by Targeting the Gut Microbial Neurotransmitter Signaling to Overcome Immunotherapy Resistance

Suppression of PD‐L1 release from small extracellular vesicles promotes systemic anti‐tumor immunity by targeting ORAI1 calcium channels

Celastrol inhibits lung cancer growth by triggering histone acetylation and acting synergically with HDAC inhibitors

Protein phase separation and its role in chromatin organization and diseases

The AKAP Cypher/Zasp contributes to β-adrenergic/PKA stimulation of cardiac CaV1.2 calcium channels

Stimulation of the L-type Ca2+ current conducted by CaV1.2 channels in cardiac myocytes by the β-adrenergic/protein kinase A (PKA) signaling pathway requires anchoring of PKA to the CaV1.2 channel by an A-kinase anchoring protein (AKAP). However, the AKAP(s) responsible for regulation in vivo remain unknown. Here, we test the role of the AKAP Cypher/Zasp in β-adrenergic regulation of CaV1.2 channels using physiological studies of cardiac ventricular myocytes from young-adult mice lacking the long form of Cypher/Zasp (LCyphKO mice). These myocytes have increased protein levels of CaV1.2, PKA, and calcineurin. In contrast, the cell surface density of CaV1.2 channels and the basal Ca2+ current conducted by CaV1.2 channels are significantly reduced without substantial changes to kinetics or voltage dependence. β-adrenergic regulation of these L-type Ca2+ currents is also significantly reduced in myocytes from LCyphKO mice, whether calculated as a stimulation ratio or as net-stimulated Ca2+ current. At 100 nM isoproterenol, the net β-adrenergic–Ca2+ current conducted by CaV1.2 channels was reduced to 39 ± 12% of wild type. However, concentration–response curves for β-adrenergic stimulation of myocytes from LCyphKO mice have concentrations that give a half-maximal response similar to those for wild-type mice. These results identify Cypher/Zasp as an important AKAP for β-adrenergic regulation of cardiac CaV1.2 channels. Other AKAPs may work cooperatively with Cypher/Zasp to give the full magnitude of β-adrenergic regulation of CaV1.2 channels observed in vivo.

Fatty-acyl chain profiles of cellular phosphoinositides

Osmoregulatory inositol transporter SMIT1 modulates electrical activity by adjusting PI(4,5)P ₂ levels

Significance Cells living in variable environments evolve ways to adapt to altered extracellular conditions. During hypertonic stress, the expression of several human osmolyte transporters increases, thereby accumulating more osmolytes and elevating intracellular osmolarity. We focused on one of these osmolytes, myo-inositol, which is also the precursor of membrane phosphoinositide lipids. We found that intracellular accumulation of myo-inositol via its transporter SMIT1 is able to increase phosphoinositide levels and thereby modulate the activities of phosphoinositide-dependent ion channels. We provide evidence for a previously unidentified connection between the extracellular osmotic changes and the electrical properties of excitable cells. Our findings may help elucidate mechanisms underlying several diseases characterized by either perturbed myo-inositol levels or increased extracellular tonicity.

2-Aminoethoxydiphenyl Borate Potentiates CRAC Current by Directly Dilating the Pore of Open Orai1

High Membrane Permeability for Melatonin

GABAergic signaling in the rat pineal gland

Loss of β-adrenergic–stimulated phosphorylation of Ca _V 1.2 channels on Ser1700 leads to heart failure

Significance Calcium entry initiates contraction in cardiac myocytes, and altered expression of voltage-gated calcium channel 1.2 (Ca V 1.2) causes heart failure in mice. Here we show that reducing β-adrenergic regulation of Ca V 1.2 by mutation of a PKA site in the C-terminal domain causes age-related heart failure. Dual mutation of a nearby casein-kinase II phosphorylation site accelerated heart failure. The PKA level was increased; PKA-mediated phosphorylation of ryanodine receptor type-2, phospholamban, and troponin-I was increased; the calcium pool in the sarcoplasmic reticulum was increased; and the activity of the calcium-dependent phosphoprotein phosphatase calcineurin was persistently elevated. These changes in mice with a mutation at the PKA site Ser1700 (SA mice) suggest that compensatory mechanisms may initially enhance contractility but eventually cause increased sensitivity to cardiovascular stress and heart failure.

Noradrenaline upregulates T-type calcium channels in rat pinealocytes

N-Myc-induced up-regulation of TRPM6/TRPM7 channels promotes neuroblastoma cell proliferation

The TRPM6 Kinase Domain Determines the Mg·ATP Sensitivity of TRPM7/M6 Heteromeric Ion Channels

TRPM7 is regulated by halides through its kinase domain

Trimethyltin Chloride Induced Chlorde Secretion across the Rat Distal Colon

Cellular Mechanisms Underlying the Laxative Effect of Flavonol Naringenin on Rat Constipation Model