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.

Scalaradial Is a Potent Inhibitor of Transient Receptor Potential Melastatin 2 (TRPM2) Ion Channels.

TRPM2 is a Ca-permeable, nonselective cation channel that plays a role in oxidant-induced cell death, insulin secretion, and cytokine release. Few TRPM2 inhibitors have been reported, which hampers the validation of TRPM2 as a drug target. While screening our in-house marine-derived chemical library, we identified scalaradial and 12-deacetylscalaradial as the active components within an extract of an undescribed species of Cacospongia (class Demospongiae, family Thorectidae) that strongly inhibited TRPM2-mediated Ca influx in TRPM2-overexpressing HEK293 cells.

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.

The calcium-permeable non-selective cation channel TRPM2 is modulated by cellular acidification.

TRPM2 is a calcium-permeable non-selective cation channel expressed in the plasma membrane and in lysosomes that is critically involved in aggravating reactive oxygen species (ROS)-induced inflammatory processes and has been implicated in cell death. TRPM2 is gated by ADP-ribose (ADPR) and modulated by physiological processes that produce peroxide, cyclic ADP-ribose (cADPR), nicotinamide adenine dinucleotide phosphate (NAADP) and Ca(2+). We investigated the role of extra- and intracellular acidification on heterologously expressed TRPM2 in HEK293 cells.

The amiodarone derivative KB130015 activates hERG1 potassium channels via a novel mechanism.

Human ether à go-go related gene (hERG1) potassium channels underlie the repolarizing I(Kr) current in the heart. Since they are targets of various drugs with cardiac side effects we tested whether the amiodarone derivative 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015) blocks hERG1 channels like its parent compound. Using patch-clamp and two-electrode voltage-clamp techniques we found that KB130015 blocks native and recombinant hERG1 channels at high voltages, but it activates them at low voltages.

Regulation of TRPM2 by extra- and intracellular calcium.

TRPM2 is a calcium-permeable nonselective cation channel that is opened by the binding of ADP-ribose (ADPR) to a C-terminal nudix domain. Channel activity is further regulated by several cytosolic factors, including cyclic ADPR (cADPR), nicotinamide adenine dinucleotide phosphate (NAADP), Ca(2+) and calmodulin (CaM), and adenosine monophosphate (AMP). In addition, intracellular ions typically used in patch-clamp experiments such as Cs(+) or Na(+) can alter ADPR sensitivity and voltage dependence, complicating the evaluation of the roles of the various modulators in a physiological context.

pH-dependent modulation of Kv1.3 inactivation: role of His399.

The Kv1.3 K(+) channel lacks N-type inactivation, but during prolonged depolarized periods it inactivates via the slow (P/C type) mechanism. It bears a titratable histidine residue in position 399 (equivalent of Shaker 449), a site known to influence the rate of slow inactivation.

Mechanisms of the inhibition of Shaker potassium channels by protons.

Potassium channels are regulated by protons in various ways and, in most cases, acidification results in potassium current reduction. To elucidate the mechanisms of proton-channel interactions we investigated N-terminally truncated Shaker potassium channels (Kv1 channels) expressed in Xenopus oocytes, varying pH at the intracellular and the extracellular face of the membrane. Intracellular acidification resulted in rapid and reversible channel block.

Cations affect the rate of gating charge recovery in wild-type and W434F Shaker channels through a variety of mechanisms.

In this study we examine the effects of ionic conditions on the gating charge movement in the fast inactivation-removed wild-type Shaker channel and its W434F mutant. Our results show that various ionic conditions influence the rate at which gating charge returns during repolarization following a depolarizing pulse. These effects are realized through different mechanisms, which include the regulation of channel closing by occupying the cavity, the modulation of transitions into inactivated states, and effects on transitions between closed states via a direct interaction with the channel's gating charges.