Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice.

The mechanisms of pancreatic pain, a cardinal symptom of pancreatitis, are unknown. Proinflammatory agents that activate transient receptor potential (TRP) channels in nociceptive neurons can cause neurogenic inflammation and pain. We report a major role for TRPV4, which detects osmotic pressure and arachidonic acid metabolites, and TRPA1, which responds to 4-hydroxynonenal and cyclopentenone prostaglandins, in pancreatic inflammation and pain in mice. Immunoreactive TRPV4 and TRPA1 were detected in pancreatic nerve fibers and in dorsal root ganglia neurons innervating the pancreas, which were identified by retrograde tracing. Agonists of TRPV4 and TRPA1 increased intracellular Ca(2+) concentration ([Ca(2+)](i)) in these neurons in culture, and neurons also responded to the TRPV1 agonist capsaicin and are thus nociceptors. Intraductal injection of TRPV4 and TRPA1 agonists increased c-Fos expression in spinal neurons, indicative of nociceptor activation, and intraductal TRPA1 agonists also caused pancreatic inflammation. The effects of TRPV4 and TRPA1 agonists on [Ca(2+)](i), pain and inflammation were markedly diminished or abolished in trpv4 and trpa1 knockout mice. The secretagogue cerulein induced pancreatitis, c-Fos expression in spinal neurons, and pain behavior in wild-type mice. Deletion of trpv4 or trpa1 suppressed c-Fos expression and pain behavior, and deletion of trpa1 attenuated pancreatitis. Thus TRPV4 and TRPA1 contribute to pancreatic pain, and TRPA1 also mediates pancreatic inflammation. Our results provide new information about the contributions of TRPV4 and TRPA1 to inflammatory pain and suggest that channel antagonists are an effective therapy for pancreatitis, when multiple proinflammatory agents are generated that can activate and sensitize these channels.

Diverse mechanisms underlying the regulation of ion channels by carbon monoxide

Carbon monoxide is firmly established as an important, physiological signalling molecule as well as a potent toxin. Through its ability to bind metal-containing proteins it is known to interfere with a number of intracellular signalling pathways, and such actions can account for its physiological and pathological effects. In particular, CO can modulate the intracellular production of reactive oxygen species, nitric oxide and cGMP levels, as well as regulate MAP kinase signalling. In this review, we consider ion channels as more recently discovered effectors of CO signalling. CO is now known to regulate a growing number of different ion channel types, and detailed studies of the underlying mechanisms of action are revealing unexpected findings. For example, there are clear areas of contention surrounding its ability to increase the activity of high conductance, Ca2+ -sensitive K+ channels. More recent studies have revealed the ability of CO to inhibit T-type Ca2+ channels and have unveiled a novel signalling pathway underlying tonic regulation of this channel. It is clear that the investigation of ion channels as effectors of CO signalling is in its infancy, and much more work is required to fully understand both the physiological and the toxic actions of this gas. Only then can its emerging use as a therapeutic tool be fully and safely exploited.

Diverse mechanisms underlying the regulation of ion channels by carbon monoxide

Carbon monoxide (CO) is firmly established as an important, physiological signalling molecule as well as a potent toxin. Through its ability to bind metal-containing proteins, it is known to interfere with a number of intracellular signalling pathways, and such actions can account for its physiological and pathological effects. In particular, CO can modulate the intracellular production of reactive oxygen species, NO and cGMP levels, as well as regulate MAPK signalling. In this review, we consider ion channels as more recently discovered effectors of CO signalling. CO is now known to regulate a growing number of different ion channel types, and detailed studies of the underlying mechanisms of action are revealing unexpected findings. For example, there are clear areas of contention surrounding its ability to increase the activity of high conductance, Ca2+ -sensitive K+ channels. More recent studies have revealed the ability of CO to inhibit T-type Ca2+ channels and have unveiled a novel signalling pathway underlying tonic regulation of this channel. It is clear that the investigation of ion channels as effectors of CO signalling is in its infancy, and much more work is required to fully understand both the physiological and the toxic actions of this gas. Only then can its emerging use as a therapeutic tool be fully and safely exploited.

Oxygen-dependent hydroxylation by Factor Inhibiting HIF (FIH) regulates the TRPV3 ion channel

Factor Inhibiting HIF (FIH) is an oxygen-dependent asparaginyl hydroxylase that regulates the hypoxia-inducible factors (HIFs). Several proteins containing ankyrin repeat domains have been characterised as substrates of FIH, although there is little evidence for a functional consequence of hydroxylation on these substrates. This study demonstrates that the transient receptor potential vanilloid 3 (TRPV3) channel is hydroxylated by FIH on asparagine 242 within the cytoplasmic ankyrin repeat domain. Hypoxia, FIH inhibitors and mutation of asparagine 242 all potentiated TRPV3-mediated current, without altering TRPV3 protein levels, indicating that oxygen-dependent hydroxylation inhibits TRPV3 activity. This novel mechanism of channel regulation by oxygendependent asparaginyl hydroxylation is likely to extend to other ion channels.

A comparison between ion characteristics observed by the POLAR and DMSP spacecraft in the high-latitude magnetosphere

We study here the injection and transport of ions in the convection-dominated region of the Earth’s magnetosphere. The total ion counts from the CAMMICE MICS instrument aboard the POLAR spacecraft are used to generate occurrence probability distributions of magnetospheric ion populations. MICS ion spectra are characterised by both the peak in the differential energy flux, and the average energy of ions striking the detector. The former permits a comparison with the Stubbs et al. (2001) survey of He2+ ions of solar wind origin within the magnetosphere. The latter can address the occurrences of various classifications of precipitating particle fluxes observed in the topside ionosphere by DMSP satellites (Newell and Meng, 1992). The peak energy occurrences are consistent with our earlier work, including the dawn-dusk asymmetry with enhanced occurrences on the dawn flank at low energies, switching to the dusk flank at higher energies. The differences in the ion energies observed in these two studies can be explained by drift orbit effects and acceleration processes at the magnetopause, and in the tail current sheet. Near noon at average ion energies of _1 keV, the cusp and open LLBL occur further poleward here than in the Newell and Meng survey, probably due to convectionrelated time-of-flight effects. An important new result is that the pre-noon bias previously observed in the LLBL is most likely due to the component of this population on closed field lines, formed largely by low energy ions drifting earthward from the tail. There is no evidence here of mass and momentum transfer from the solar wind to the LLBL by nonreconnection coupling. At higher energies (_2–20 keV), we observe ions mapping to the auroral oval and can distinguish between the boundary and central plasma sheets. We show that ions at these energies relate to a transition from dawnward to duskward dominated flow, this is evidence of how ion drift orbits in the tail influence the location and behaviour of the plasma populations in the magnetosphere.

The dependence of cusp ion signatures on the reconnection rate

The interpretation of structure in cusp ion dispersions is important for helping to understand the temporal and spatial structure of magnetopause reconnection. “Stepped” and “sawtooth” signatures have been shown to be caused by temporal variations in the reconnection rate under the same physical conditions for different satellite trajectories. The present paper shows that even for a single satellite path, a change in the amplitude of any reconnection pulses can alter the observed signature and even turn sawtooth into stepped forms and vice versa. On 20 August 1998, the Defense Meteorological Satellite Program (DMSP) craft F-14 crossed the cusp just to the south of Longyearbyen, returning on the following orbit. The two passes by the DMSP F-14 satellites have very similar trajectories and the open-closed field line boundary (OCB) crossings, as estimated from the SSJ/4 precipitating particle data and Polar UVI images, imply a similarly-shaped polar cap, yet the cusp ion dispersion signatures differ substantially. The cusp crossing at 08:54 UT displays a stepped ion dispersion previously considered to be typical of a meridional pass, whereas the crossing at 10:38 UT is a sawtooth form ion dispersion, previously considered typical of a satellite travelling longitudinally with respect to the OCB. It is shown that this change in dispersed ion signature is likely to be due to a change in the amplitude of the pulses in the reconnection rate, causing the stepped signature. Modelling of the low-energy ion cutoff under different conditions has reproduced the forms of signature observed.

Cusp ion steps, field-aligned currents and poleward moving auroral forms

We predict the field-aligned currents around cusp ion steps produced by pulsed reconnection between the geomagnetic field and an interplanetary magnetic field (IMF) with a B-Y component that is large in magnitude. For B-Y > 0, patches of newly opened flux move westward and eastward in the Northern and Southern Hemispheres, respectively, under the influence of the magnetic curvature force. These flow directions are reversed for B-Y < 0. The speed of this longitudinal motion initially grows with elapsed time since reconnection, but then decays as the newly opened field lines straighten. We predict sheets of field-aligned current on the boundaries between the patches produced by successive reconnection pulses, associated with the difference in the speeds of their longitudinal motion. For low elapsed times since reconnection, near the equatorward edge of the cusp region where the field lines are accelerating, the field-aligned current sheets will be downward or upward in both hemispheres for positive or negative IMF B-Y, respectively. At larger elapsed times since reconnection, as events slow and evolve from the cusp into the mantle region, these field-aligned current directions will be reversed. Observations by the Polar spacecraft on August 26,1998, show the predicted upward current sheets at steps seen in the mantle region for IMF B-Y > 0. Mapped into the ionosphere, the steps coincide with poleward moving events seen by the CUTLASS HF radar. The mapped location of the largest step also coincides with a poleward moving arc seen by the UVI imager on Polar. We show that the arc is consistent with a region of upward field-aligned current that has become unstable, such that a potential drop of about 1 kV formed below the spacecraft. The importance of these observations is that they confirm that the poleward moving events, as seen by the HF radar and the UV imager, are due to pulsed magnetopause reconnection. Milan et al. [2000] noted that the great longitudinal extent of these events means that the required reconnection pulses would have contributed almost all the voltage placed across the magnetosphere at this time. The observations also show that auroral arcs can form on open field lines in response to the pulsed application of voltage at the magnetopause.

Ionospheric ion and electron heating at the poleward boundary of a poleward expanding substorm-disturbed region

We present observations of a poleward propagating substorm-disturbed region which was observed by the European Incoherent SCATter (EISCAT) radar and the Svalbard International Monitor for Auroral Geomagnetic Effects (IMAGE) magnetometers in the postmidnight sector. The expansion of the disturbance was launched by a substorm intensification which started similar to 25 min after the initial onset, and similar to 10 min before the disturbance arrived over Svalbard. In association with the magnetic disturbance, a poleward expanding enduring enhancement in the F region electron temperature was observed, indicative of soft electron precipitation, with a narrow band of enhanced ion temperature straddling its poleward edge, indicative of fast ion flows and ion-neutral collisional heating. This electron temperature boundary was coincident with the poleward propagating electrojet current system detected by the high-latitude IMAGE magnetometer stations and is taken to be a proxy for the observation of a substorm auroral bulge. The electron temperature boundary is inferred to have a width comparable or less than one radar range gate (similar to 60 km transverse to the magnetic field), while the region of high ion temperature was found to be approximately three gates wide, extending approximately two gates (similar to 120 km) poleward of the electron temperature boundary, and approximately one gate (similar to 60 km) equatorward. The two-beam radar line-of-sight velocity data are found to be consistent with the existence of a layer of high-speed flow in the boundary, peaking at values similar to1.5-3 km s(-1), roughly consistent with the ion temperature data. The flow is directed either east or west along the boundary depending on the direction of the flow in the poleward region. We infer that the flow is deflected along and around the boundary of the substorm-disturbed region due to the high conductivity of the latter. Variations in the flow poleward of the boundary produced no discernible magnetic effects on the ground, confirming the low conductivity of the preboundary ionosphere.

Modelling signatures of pulsed magnetopause reconnection in cusp ion dispersion signatures seen at middle altitudes

It is shown that the open magnetosphere model can reproduce both the down-going and the up-going magnetosheath ions seen in the cusp and mantle regions by the Polar satellite at middle altitudes. ?he pass studied shows a series of discontinuities in the ion dispersion, most of which are shown to arise from pulses of magnetopause reconnection rate. A total of 9 pulses are detected in an interval estimated to be about 30 min long, giving a mean repetition period of about 3 min: they vary in length between 0.5 min and 3.5 min and are separated by periods of much slower reconnection of duration 1-3 min. One step is not as predicted for reconnection rate pulses but is explained in terms of compressive motions caused by a pulse of solar wind dynamic pressure. The reconnection site is found to be 16 +/- 3 R-E from the ionosphere along the separatrix field line, placing it at low latitudes on the dayside magnetopause.

Ion populations on open field lines within the dayside low-latitude boundary layer: theory and observations during a transient event

We analyze of ion populations observed by the NOAA-12 satellite within dayside auroral transients. The data are matched with an open magnetopause model which allows for the transmission of magnetosheath ions across one or both of the two Alfvén waves which emanate from the magnetopause reconnection site. It also allows for reflection and acceleration of ions of magnetospheric origin by these waves. From the good agreement found between the model and the observations, we propose that the events and the low-latitude boundary precipitation are both on open field lines.

Ion acceleration at both the interior and exterior Alfvén waves associated with the magnetopause reconnection site: Signatures in cusp precipitation

We present evidence for the acceleration of magnetospheric ions by reflection off two Alfvén waves, launched by the reconnection site into the inflow regions on both sides of the reconnecting magnetopause. The “exterior” wave stands in the inflow from the magnetosheath and is the magnetopause, in the sense that the majority of the field rotation occurs there. The other, “interior” wave stands in the inflow region on the magnetospheric side of the boundary. The population reflected by the interior wave is the more highly energized of the two and appears at low altitudes on open field lines, immediately equatorward of the cusp precipitation. In addition, we identify the population of magnetosheath ions transmitted across the exterior Alfvén wave, as well as a population of magnetospheric ions which are accelerated, after transmission through the interior wave, by reflection off the exterior wave. The ion populations near the X line are modeled and, with allowance for time-of-flight effects, are also derived from observations in the dayside auroral ionosphere. Agreement between observed and theoretical spectra is very good and the theory also explains the observed total fluxes and average energies of the precipitations poleward of the open/closed field line boundary. The results offer a physical interpretation of all the various classifications of precipitation into the dayside ionosphere (central plasma sheet, dayside boundary plasma sheet, void, low-latitude boundary layer, cusp, and mantle) and allow the conditions in both the magnetosphere and the magnetosheath adjacent to the X line to be studied.

EISCAT/CRRES observations: nightside ionospheric ion outflow and oxygen-rich substorm injections

We present combined observations made near midnight by the EISCAT radar, all-sky cameras and the combined released and radiation efects satellite (CRRES) shortly before and during a substorm. In particular, we study a discrete, equatorward-drifting auroral arc, seen several degrees poleward of the onset region. The arc passes through the field-aligned beam of the EISCAT radar and is seen to be associated with a considerable upflow of ionospheric plasma. During the substorm, the CRRES satellite observed two major injections, 17 min apart, the second of which was dominated by O+ ions. We show that the observed are was in a suitable location in both latitude and MLT to have fed O+ ions into the second injection and that the upward flux of ions associated with it was sufficient to explain the observed injection. We interpret these data as showing that arcs in the nightside plasma-sheet boundary layer could be the source of O+ ions energised by a dipolarisation of the mid- and near-Earth tail, as opposed to ions ejected from the dayside ionosphere in the cleft ion fountain.

An analysis of the accuracy of magnetopause reconnection rate variations deduced from cusp ion dispersion characteristics

We present an analysis of the accuracy of the method introduced by Lockwood et al. (1994) for the determination of the magnetopause reconnection rate from the dispersion of precipitating ions in the ionospheric cusp region. Tests are made by applying the method to synthesised data. The simulated cusp ion precipitation data are produced by an analytic model of the evolution of newly-opened field lines, along which magnetosheath ions are firstly injected across the magnetopause and then dispersed as they propagate into the ionosphere. The rate at which these newly opened field lines are generated by reconnection can be varied. The derived reconnection rate estimates are then compared with the input variation to the model and the accuracy of the method assessed. Results are presented for steady-state reconnection, for continuous reconnection showing a sine-wave variation in rate and for reconnection which only occurs in square wave pulses. It is found that the method always yields the total flux reconnected (per unit length of the open-closed field-line boundary) to within an accuracy of better than 5%, but that pulses tend to be smoothed so that the peak reconnection rate within the pulse is underestimated and the pulse length is overestimated. This smoothing is reduced if the separation between energy channels of the instrument is reduced; however this also acts to increase the experimental uncertainty in the estimates, an effect which can be countered by improving the time resolution of the observations. The limited time resolution of the data is shown to set a minimum reconnection rate below which the method gives spurious short-period oscillations about the true value. Various examples of reconnection rate variations derived from cusp observations are discussed in the light of this analysis.

Overlapping cusp ion injections: An explanation invoking magnetopause reconnection

An explanation of overlapping cusp ion injections is presented using the pulsating cusp model of the effects of magnetopause reconnection. It is shown that two populations of cusp ions, covering separated energy ranges, can be seen simultaneously by low- or mid-altitude satellites because of the combined effect of the acceleration and the straightening of newly-opened field lines as they evolve away from the reconnection site. Observations of such signatures, recently reported in data from the Viking and Freja satellites, are discussed in terms of pulsed and steady reconnection.

High-latitude ion transport and energetic explorer (HI-LITE): a mission to investigate ion outflow from the high-latitude ionosphere

The proposed HI-LITE Explorer will investigate the global ion outflow from the high-latitude ionosphere, its relationship to auroral features, and the consequences of this outflow on magnetospheric processes. The unique nature of the HI-LITE Explorer images will allow temporal and spatial features of the global ion outflow to be determined. The mission's scientific motivation comes from the fundamental role high-latitude ionospheric ions play in the dynamics of the solar wind driven magnetospheric-ionospheric system. These outflows are a major source of plasma for the magnetosphere and it is believed they play an important role in the triggering of substorms. In addition this paper describes the HI-LITE spacecraft and instruments.