Adenosine, a purine nucleoside, is present at high concentrations in tumors where it contributes to the failure of immune cells to eliminate cancer cells. The mechanisms responsible for the immunosuppressive properties of adenosine are not fully understood. We tested the hypothesis that adenosine’s immunosuppressive functions in human T lymphocytes are in part mediated via modulation of ion channels. The activity of T lymphocytes relies on ion channels. KCa3.1 and Kv1.3 channels control cytokine release and, together with TRPM7, regulate T cell motility. Adenosine selectively inhibited KCa3.1, but not Kv1.3 and TRPM7, in activated human T cells. This effect of adenosine was mainly mediated by A2A receptors as KCa3.1 inhibition was reversed by SCH58261 (selective A2A receptor antagonist), but not by MRS1754 (A2B receptor antagonist) and it was mimicked by the A2A receptor agonist CGS21680. Furthermore, it was mediated by the cAMP/PKAI signaling pathway as adenylyl-cyclase and PKAI inhibition prevented adenosine effect on KCa3.1. The functional implication of the effect of adenosine on KCa3.1 was determined by measuring T cell motility on ICAM-1 surfaces. Adenosine and CGS21680 inhibited T cell migration. Comparable effects were obtained by KCa3.1 blockade with TRAM-34. Furthermore, the effect of adenosine on cell migration was abolished by pre-exposure to TRAM-34. Additionally, adenosine suppresses IL-2 secretion via KCa3.1 inhibition. Our data indicate that adenosine inhibits KCa3.1 in human T cells via A2A receptor and PKAI thereby resulting in decreased T cell motility and cytokine release. This mechanism is likely to contribute to decreased immune surveillance in solid tumors.

Background: Ion channels are candidate molecules for transforming external stimuli into neural activity during sensory perception. Results: Pickpocket1 encodes an acid-sensing ion channel (ASIC) that is sufficient to drive neural activity in sensory neurons. Conclusion:The perception of external acid by Pickpocket1 channels is sufficient to produce phasic sensory neuron activity. Significance: ASIC channels can function as molecular sensory transducers in sensory neurons.

The immunological synapse (IS), a highly organized structure that forms at the point of contact between a T cell and an APC, is essential for the proper development of signaling events, including the Ca2+ response. Kv1.3 channels control Ca2+ homeostasis in human T cells and move into the IS upon Ag presentation. However, the process involved in channel accumulation in the IS and the functional implications of this localization are not yet known. Here we define the movement of Kv1.3 into the IS and study whether Kv1.3 localization into the IS influences Ca2+ signaling in Jurkat T cells. Crosslinking of the channel protein with an extracellular Ab limits Kv1.3 mobility and accumulation at the IS. Moreover, Kv1.3 recruitment to the IS does not involve the transport of newly synthesized channels and it does not occur through recycling of membrane channels. Kv1.3 localization in the IS modulates the Ca2+ response. Blockade of Kv1.3 movement into the IS by crosslinking significantly increases the amplitude of the Ca2+ response triggered by anti-CD3/anti-CD28-coated beads, which induce the formation of the IS. On the contrary, the Ca2+ response induced by TCR stimulation without the formation of the IS with soluble anti-CD3/anti-CD28 Abs is unaltered. The results presented herein indicate that, upon Ag presentation, membrane-incorporated Kv1.3 channels move along the plasma membrane to localize in the IS. This localization is important to control the amplitude of the Ca2+ response, and disruption of this process can account for alterations of downstream Ca2+-dependent signaling events.

Acute experiments on decerebrate cats were performed to study the mechanism of formation of the locomotor pattern in conditions of epidural stimulation of the spinal cord. These studies showed that only segments L3-L5 contributed to generating the stepping pattern in the hindlimbs. At the optimum frequency (5-10 Hz) of stimulation of these segments, formation of electromyographic burst activity in the flexor muscles was mainly due to polysynaptic reflex responses with latencies of 80-110 msec. In the extensor muscles, this process involved the interaction of a monosynaptic reflex and polysynaptic activity. In epidural stimulation, the stepping pattern was specified by spinal structures, while peripheral feedback had modulatory influences.

Discretionary control of Na(+) excretion is a key component of the regulation of arterial blood pressure in mammals. Sodium excretion is fine-tuned in the aldosterone-sensitive distal nephron by the activity of the epithelial Na(+) channel (ENaC). Here, ENaC functions as a final effector of the renin-angiotensin-aldosterone system (RAAS) during negative feedback control of blood pressure. Mutations affecting ENaC activity and abnormal regulation of this channel affect blood pressure through pathological changes to Na(+) excretion. Recent evidence demonstrates that powerful signalling pathways function in parallel with the RAAS to modulate ENaC activity and blood pressure. An inclusive paradigm is emerging with respect to regulation of blood pressure where ENaC serves as a critical point of convergence for several important signalling systems that affect renal Na(+) excretion. A robust inhibitory purinergic signalling system intrinsic to the distal nephron dynamically regulates ENaC through paracrine ATP signalling via the metabotropic P2Y2 purinergic receptor to properly match urinary Na(+) excretion to dietary Na(+) intake. This enables blood pressure to be maintained within a normal range despite broad changes in dietary Na(+) consumption. Loss of purinergic inhibition of ENaC increases blood pressure by causing inappropriate Na(+) excretion. In contrast, stimulation of the P2Y2 receptor promotes natriuresis and a decrease in blood pressure. Such observations identify purinergic signalling in the distal nephron as possibly causative, when dysfunctional, for certain forms of elevated blood pressure, and as a possible therapeutic target for the treatment of elevated blood pressure particularly that associated with salt sensitivity.