Acidic Cannabinoids Suppress Proinflammatory Cytokine Release by Blocking Store-operated Calcium Entry.

has long been known to affect numerous biological activities. Although plant extracts, purified cannabinoids, or synthetic cannabinoid analogs have shown therapeutic potential in pain, inflammation, seizure disorders, appetite stimulation, muscle spasticity, and treatment of nausea/vomiting, the underlying mechanisms of action remain ill-defined. In this study we provide the first comprehensive overview of the effects of whole-plant extracts and various pure cannabinoids on store-operated calcium (Ca) entry (SOCE) in several different immune cell lines.

Pharmacology of JNJ-28583113: A novel TRPM2 antagonist.

Transient receptor potential melastatin type 2 (TRPM2) is a cation channel activated by free intracellular ADP-ribose and reactive oxygen species. TRPM2 signaling has been linked to the pathophysiology of CNS disorders such as neuropathic pain, bipolar disorder and Alzheimer's disease. In this manuscript, we describe the discovery of JNJ-28583113, a potent brain penetrant TRPM2 antagonist.

Areca nut extracts mobilize calcium and release pro-inflammatory cytokines from various immune cells.

Betel nut consumption has significant implications for the public health globally, as the wide-spread habit of Areca chewing throughout Asia and the Pacific is associated with a high prevalence of oral carcinoma and other diseases. Despite a clear causal association of betel nut chewing and oral mucosal diseases, the biological mechanisms that link Areca nut-contained molecules, inflammation and cancer remain underexplored. In this study we show that the whole Areca nut extract (ANE) is capable of mobilizing Ca in various immune cell lines.

Inhibition of TRPM7 suppresses cell proliferation of colon adenocarcinoma in vitro and induces hypomagnesemia in vivo without affecting azoxymethane-induced early colon cancer in mice.

Background: Magnesium (Mg) is an essential cation implicated in carcinogenesis, solid tumor progression and metastatic potential. The Transient Receptor Potential Melastatin Member 7 (TRPM7) is a divalent ion channel involved in cellular and systemic Mg homeostasis. Abnormal expression of TRPM7 is found in numerous cancers, including colon, implicating TRPM7 in this process.

The TRPM7 channel kinase regulates store-operated calcium entry.

Key Points: Pharmacological and molecular inhibition of transient receptor potential melastatin 7 (TRPM7) reduces store-operated calcium entry (SOCE). Overexpression of TRPM7 in TRPM7 cells restores SOCE. TRPM7 is not a store-operated calcium channel.

Functional cooperation between KCa3.1 and TRPC1 channels in human breast cancer: Role in cell proliferation and patient prognosis.

Intracellular Ca2+ levels are important regulators of cell cycle and proliferation. We, and others, have previously reported the role of KCa3.1 (KCNN4) channels in regulating the membrane potential and the Ca2+ entry in association with cell proliferation.

State-dependent blocking mechanism of Kv 1.3 channels by the antimycobacterial drug clofazimine.

Background And Purpose: Kv 1.3 potassium channels are promising pharmaceutical targets for treating immune diseases as they modulate Ca(2+) signalling in T cells by regulating the membrane potential and with it the driving force for Ca(2+) influx. The antimycobacterial drug clofazimine has been demonstrated to attenuate antigen-induced Ca(2+) oscillations, suppress cytokine release and prevent skin graft rejection by inhibiting Kv 1.

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

Intracellular levels of the divalent cations Ca2+ and Mg2+ are important regulators of cell cycle and proliferation. However, the precise mechanisms by which they are regulated in cancer remain incompletely understood. The channel kinases TRPM6 and TRPM7 are gatekeepers of human Ca2+/Mg2+ metabolism.

TRPM2.

TRPM2 is the second member of the transient receptor potential melastatin-related (TRPM) family of cation channels. The protein is widely expressed including in the brain, immune system, endocrine cells, and endothelia. It embodies both ion channel functionality and enzymatic ADP-ribose (ADPr) hydrolase activity.

The TRPM6 kinase domain determines the Mg·ATP sensitivity of TRPM7/M6 heteromeric ion channels.

The transient receptor potential melastatin member 7 (TRPM7) and member 6 (TRPM6) are divalent cation channel kinases essential for magnesium (Mg(2+)) homeostasis in vertebrates. It remains unclear how TRPM6 affects divalent cation transport and whether this involves functional homomeric TRPM6 plasma membrane channels or heteromeric channel assemblies with TRPM7. We show that homomeric TRPM6 is highly sensitive to intracellular free Mg(2+) and therefore unlikely to be active at physiological levels of [Mg(2+)]i.

ORAI3 silencing alters cell proliferation and cell cycle progression via c-myc pathway in breast cancer cells.

Members of the Orai family are highly selective calcium ion channels that play an important role in store-operated calcium entry. Among the three known Orai isoforms, Orai3 has gained increased attention, notably for its emerging role in cancer. We recently demonstrated that Orai3 channels are over-expressed in breast cancer (BC) biopsies, and involved specifically in proliferation, cell cycle progression and survival of MCF-7 BC cells.

High expression of transient receptor potential channels in human breast cancer epithelial cells and tissues: correlation with pathological parameters.

Background: Transient Receptor Potential (TRP) channels are expressed in many solid tumors. However, their expression in breast cancer remains largely unknown. Here, we investigated the profile expression of 13 TRP channels in human breast ductal adenocarcinoma (hBDA) and performed a correlation between their overexpression and pathological parameters.

Intermediate conductance Ca2+ activated K+ channels are expressed and functional in breast adenocarcinomas: correlation with tumour grade and metastasis status.

K+ channels are key molecules in the progression of several cancer types and are considered to be potential targets for cancer therapy. In this study, we investigated the intermediate- conductance Ca2+-activated K+ channels (hKCa3.1) expression in both breast carcinoma (BC) specimens and human breast cancer epithelial primary cell cultures (hBCE) using immuno-histochemistry (60 samples), quantitative Real-Time RT-PCR (30 samples) and Western blot assay (30 samples).

Down-regulation of Orai3 arrests cell-cycle progression and induces apoptosis in breast cancer cells but not in normal breast epithelial cells.

Breast cancer (BC) is the leading cancer in the world in terms of incidence and mortality in women. However, the mechanism by which BC develops remains largely unknown. The increase in cytosolic free Ca(2+) can result in different physiological changes including cell growth and death.

Intermediate Ca2+-sensitive K+ channels are necessary for prolactin-induced proliferation in breast cancer cells.

Prolactin (PRL) is a polypeptidic hormone which acts both systemically and locally to cause lactation by interacting with the PRL receptor, a Janus kinase (JAK2)-coupled cytokine receptor family member. Several studies have reported that serum PRL level elevation is associated with an increased risk for breast cancer, and evidence has suggested that PRL is one actor in the pathogenesis and progression of this cancer. We previously reported the involvement of hIKCa1 in breast cell cycle progression and cell proliferation.