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Myocardial-restricted ablation of the GTPase RAD results in a pro-adaptive heart response in mice.

Existing therapies to improve heart function target β-adrenergic receptor (β-AR) signaling and Ca2+ handling and often lead to adverse outcomes. This underscores an unmet need for positive inotropes that improve heart function without any adverse effects. The GTPase Ras associated with diabetes (RAD) regulates L-type Ca2+ channel (LTCC) current (ICa,L). Global RAD-knockout mice (gRAD-/-) have elevated Ca2+ handling and increased cardiac hypertrophy, but RAD is expressed also in noncardiac tissues, suggesting the possibility that pathological remodeling is due also to noncardiac effects. Here,

Tonic inhibition of TRPV3 by Mg2+ in mouse epidermal keratinocytes.

The transient receptor potential vanilloid 3 channel (TRPV3) is abundantly expressed in epidermal keratinocytes and has important roles in sensory biology and skin health. Mg(2+) deficiency causes skin disorders under certain pathological conditions such as type 2 diabetes mellitus. In this study, we investigated the effect of Mg(2+) on TRPV3 in primary epidermal keratinocytes. Extracellular Mg(2+) ([Mg(2+)](o)) inhibited TRPV3-mediated membrane current and calcium influx. TRPV3 activation induced a calcium signaling pathway culminating in activation of the cAMP response element binding. TRPV3…

The PDZ scaffold protein INAD abolishes apparent store-dependent regulation of the light-activated cation channel TRP.

In fly photoreceptor cells, light initiates a G protein-coupled phospholipase Cb-dependent signaling cascade that results in the depolarization of the cell membrane, which is mediated by the cation channels TRP and TRPL. Together with phospholipase Cb and an eye-specific protein kinase C, TRP is tethered to the scaffolding protein INAD, which forms a multimolecular signaling complex. Divergent data from expressed TRP and studies from photoreceptor cells have brought up a controversy whether or not a capacitative calcium entry (CCE) mechanism is involved in the Drosophila phototransduction path

Dihydropyridine Calcium Channel Blockers Suppress the Transcription of PD-L1 by Inhibiting the Activation of STAT1.

Programmed death ligand 1 (PD-L1) which is upregulated in various epithelial tumors, plays a central role in the evasion of the immune system. In addition to monoclonal antibodies that blocking PD1/PD-L1 axis, finding small molecule compounds that can suppress PD-L1 expression might be another substitutable strategy for PD1/PD-L1 based therapy. Here, we found that dihydropyridine calcium channel blockers dose-dependently reduced the expression of PD-L1, both in the cytoplasm and cell surface. IFNγ induced PD-L1 transcription was consistently suppressed by Lercanidipine in 24 h, whereas, the ha

Modulation of elementary calcium release mediates a transition from puffs to waves in an IP3R cluster model.

The oscillating concentration of intracellular calcium is one of the most important examples for collective dynamics in cell biology. Localized releases of calcium through clusters of inositol 1,4,5-trisphosphate receptor channels constitute elementary signals called calcium puffs. Coupling by diffusing calcium leads to global releases and waves, but the exact mechanism of inter-cluster coupling and triggering of waves is unknown. To elucidate the relation of puffs and waves, we here model a cluster of IP3R channels using a gating scheme with variable non-equilibrium IP3 binding. Hybrid stocha

[The effect of intracellular calcium on an increase in the cAMP-mediated calcium current].

Intracellularly perfused neurons of Helix pomatia in which serotonin-induced increase of calcium current (Ica) is mediated by cAMP were studied by the voltage clamp technique. It was established that an increase of the calcium intracellular concentration ([Ca2+]i) caused inhibition of the serotonin (5-HT) effect. The 5-HT effect value at 10(-6) and 10(-7) mol/l [Ca2+]i was 60 and 32% of the control one, respectively. Addition of the calmodulin antagonist (5.10(-5) M trifluoperasine) and phosphodiesterase blockers (5 mM theophylline or 10(-4) mol/l IBMX) sharply reduced the Ca2+ ability to inhi

CACNA1C is associated with auditory related fear enhancement in single prolonged stress male rats.

BACKGROUND: CACNA1C, a gene that encodes Cav 1.2 an alpha-1 subunit of L-type voltage-gated calcium channels (LTCC), has been associated with post-traumatic stress disorder (PTSD). Enhanced fear memory is a typical symptom of PTSD. The aim of the present experiment was to explore the role of calcium channels and related genes on auditory related fear in PTSD. METHOD: We employed single prolonged stress (SPS) as the animal model of PTSD in male rats. Multiple start sound amplitudes at 95 dB, 105 dB and 115 dB of Acoustic startle response (ASR) and inhibitory gating (IG) recording were used to

Prefrontal cortex excitatory neurons show distinct response to heroin-associated cue and social stimulus after prolonged heroin abstinence in mice.

Substance use disorder (SUD) has been linked with social impairments. The social cognitive dysfunctions can further increase the risk of the development of SUD or relapse. Therefore, understanding the neural mechanism of substance exposure-associated social impairments is beneficial for the development of novel prevention or treatment strategies for SUD. The prefrontal cortex (PFC) is a key brain region involved in both social cognition and drug addiction. Specifically, the prelimbic part of PFC (PrL) regulates social interaction and heroin-seeking behavior. Therefore, in this study, we explor

Blood oxygen regulation via P2Y12R expressed in the carotid body.

BACKGROUND: Peripheral blood oxygen monitoring via chemoreceptors in the carotid body (CB) is an integral function of the autonomic cardiorespiratory regulation. The presence of the purinergic P2Y12 receptor (P2Y12R) has been implicated in CB; however, the exact role of the receptor in O2 sensing and signal transduction is unknown. METHODS: The presence of P2Y12R was established by immunoblotting, RT qPCR and immunohistochemistry. Primary glomus cells were used to assess P2Y12R function during hypoxia and hypercapnia, where monoamines were measured by HPLC; calcium signal was recorded utilizi

GW0742 activates peroxisome proliferator-activated receptor δ to reduce free radicals and alleviate cardiac hypertrophy induced by hyperglycemia in cultured H9c2 cells.

Peroxisome proliferator-activated receptor δ (PPARδ), the predominant PPAR subtype in the heart, is known to regulate cardiac function. PPARδ activation may inhibit cardiac hypertrophy in H9c2 cells while the potential mechanism has not been elucidated. Then, H9c2 cells incubated with high glucose to induce hypertrophy were used to investigate using GW0742 to activate PPARδ. The fluorescence assays were applied to determine the changes in cell size, cellular calcium levels, and free radicals. Western blot analyses for hypertrophic signals and assays of messenger RNA (mRNA) levels for hypertrop

Mechanism of nitric oxide and acid-sensing ion channel 1a modulation of panic-like behaviour in the dorsal periaqueductal grey of the mouse.

Predators induce defensive responses and fear behaviours in prey. The rat exposure test (RET) is frequently used as an animal model of panic. Nitric oxide (NO) which has been reported to be activated by the NMDA receptor, in turn mediates calcium/calmodulin-dependent protein kinase II (CaMKII) signalling pathways in defensive responses. ACCN2, the orthologous human gene of acid-sensing ion channel 1a (ASIC1a), is also associated with panic disorder; however, few studies have focused on the role of ASIC1a in the modulation of panic and calcium/CaMKII signalling by NO. In the present study, NG-n

Changes in contractile protein expression are linked to ventricular stiffness in infants with pulmonary hypertension or right ventricular hypertrophy due to congenital heart disease.

BACKGROUND: The right ventricle (RV) is not designed to sustain high pressure leading to failure. There are no current medications to help RV contraction, so further information is required on adaption of the RV to such hypertension. METHODS: The Right Ventricle in Children (RVENCH) study assessed infants with congenital heart disease undergoing cardiac surgery with hypertensive RV. Clinical and echocardiographic data were recorded, and samples of RV were taken from matched infants, analysed for proteomics and compared between pathologies and with clinical and echocardiographic outcome data.

Nucleotide transmitters ATP and ADP mediate intercellular calcium wave communication via P2Y12/13 receptors among BV-2 microglia.

Nerve injury is accompanied by a liberation of diverse nucleotides, some of which act as 'find/eat-me' signals in mediating neuron-glial interplay. Intercellular Ca2+ wave (ICW) communication is the main approach by which glial cells interact and coordinate with each other to execute immune defense. However, the detailed mechanisms on how these nucleotides participate in ICW communication remain largely unclear. In the present work, we employed a mechanical stimulus to an individual BV-2 microglia to simulate localized injury. Remarkable ICW propagation was observed no matter whether calcium w

Molecular mechanisms of penile erection.

The penis physiological states of flaccidity or erection, result from the contraction or relaxation, respectively, of smooth muscle cells in the corpora cavernosa (CSMCs). They result from the interaction of various inter and intracellular molecular signaling pathways. During the more usual state of flaccidity seems to predominate a tonic sympathetic activity, releasing noradrenaline (NA) and other agonists that generate contractile signals in the CSMCs, with the likely cooperation of endothelium-derived messengers. Through activation of membrane receptors in the CSMCs they raise the intracell

Differential coupling of the P2Y1 receptor to Galpha14 and Galphaq/11 proteins during the development of the rat salivary gland.

UNLABELLED: In rat submandibular gland (SMG), the P2Y1 receptor (P2Y1R) mediates increases in the intracellular calcium concentration, [Ca2+]i that diminish as the animal ages from 1 to 4-6 weeks. However, P2Y1R mRNA levels do not change with age, suggesting that the age-dependent decrease in the [Ca2+]i response to P2Y1R agonists may be due to alterations in the activity of a component of the P2Y1R signalling pathway. OBJECTIVES: To assess whether the decrease in P2Y1R-mediated intracellular calcium signalling in SMG cells as rats age is due to a decrease in P2Y1R coupling to G proteins or t

MIZ-1 controls transcriptional programs required for BCR signaling, actin dynamics, and naïve B cell survival.

B cell receptor (BCR) signaling is required for the regulation of normal B lymphocyte development. However, many B cell lymphoma subtypes employ constitutive BCR signaling for transformation, survival, and growth. Here we report that mice expressing a POZ domain-deficient MIZ-1 (MIZ-1ΔPOZ), a well-known binding partner of the oncogene MYC, exhibit reduced surface receptor expression on naïve B cells and impaired BCR signaling. Transcriptomic and ChIP-seq analyses revealed that, in addition to autophagy related genes, MIZ-1 directly regulates genes involved in BCR signal transduction and actin

ER-mitochondria tethering and its signaling: A novel therapeutic target in breast cancer.

Communication between the endoplasmic reticulum (ER) and mitochondria through mitochondria-associated ER membranes (MAMs) is assisted by tethering proteins and signaling pathways, manifesting the dynamic exchange of lipids, calcium, and signaling molecules. However, dysregulation of tethering and signaling proteins contributes to the progression of breast cancer (BC). Abnormal MAM structures and altered ER-mitochondrial tethering impair mitochondrial functions and thereby drive BC progression. Altered mitochondrial dynamics, often characterized by dysregulated dynamin-related protein 1 (Drp1)

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… Calcium Signalling in Breast Cancer Associated Bone Pain. Int. J. Mol. Sci. 2022;23 doi: 10.3390/ijms23031902. 101. So C.L., Saunus J.M., Roberts-Thomson S.J., Monteith G.R. Calcium signalling and breast cancer. Semin. Cell Dev. Biol. 2019;94:74–83. doi: 10.1016/j.semcdb.2018.11.001. 102. … Calcium signaling in immune cells. Nat. Immunol. 2009;10:21–27. doi: 10.1038/ni.f.220. …

Crosstalk between Nitric Oxide and Bioinorganic Centers: Implications for Cellular Signaling.

Nitric oxide (NO) is one of the most extensively studied small inorganic molecules involved in biological signaling processes related to both health and disease. Many biological transformations that depend on NO rely on bioinorganic chemistry, where both redox-active and nonredox-active inorganic centers and processes play crucial roles. This review covers several key topics, including the role of heme centers in NO biosynthesis and metabolism, the function of non-heme iron in NO bioactivity, and the interplay between calcium-dependent proteins and NO signaling pathways. It also discusses the

Identification of Circular RNAs of Testis and Caput Epididymis and Prediction of Their Potential Functional Roles in Donkeys.

Circular RNAs (circRNAs) are a class of noncoding RNAs with a covalently closed loop. Studies have demonstrated that circRNA can function as … articipated in the TGF-β signaling pathway, GnRH signaling pathway, estrogen signaling pathway, and calcium signaling pathway. Our discoveries provide a solid foundation for identifying and characterizing critical circRNAs involved in testis development or spermatogenesis.

Molecular Mechanisms of Functional Adrenocortical Adenoma and Carcinoma: Genetic Characterization and Intracellular Signaling Pathway.

The adrenal cortex produces steroid hormones as adrenocortical hormones in the body, secreting mineralocorticoids, glucocorticoids, and adre … ecially ion channels, resulting in hypersecretion of aldosterone due to activation of intracellular calcium signaling. In addition, somatic mutations have been detected in those encoding cAMP-PKA signaling-related factors, resulting in hypersecretion of cortisol due to its driven status in CPAs. In ACC, mutations in tumor suppressor genes and Wnt-β-catenin signalin …