Hair cells use active zones with different voltage dependence of Ca²⁺ influx to decompose sounds into complementary neural codes.

For sounds of a given frequency, spiral ganglion neurons (SGNs) with different thresholds and dynamic ranges collectively encode the wide range of audible sound pressures. Heterogeneity of synapses between inner hair cells (IHCs) and SGNs is an attractive candidate mechanism for generating complementary neural codes covering the entire dynamic range. Here, we quantified active zone (AZ) properties as a function of AZ position within mouse IHCs by combining patch clamp and imaging of presynaptic Ca2+ influx and by immunohistochemistry. We report substantial AZ heterogeneity whereby the voltage of half-maximal activation of Ca2+ influx ranged over ∼20 mV. Ca2+ influx at AZs facing away from the ganglion activated at weaker depolarizations. Estimates of AZ size and Ca2+ channel number were correlated and larger when AZs faced the ganglion. Disruption of the deafness gene GIPC3 in mice shifted the activation of presynaptic Ca2+ influx to more hyperpolarized potentials and increased the spontaneous SGN discharge. Moreover, Gipc3 disruption enhanced Ca2+ influx and exocytosis in IHCs, reversed the spatial gradient of maximal Ca2+ influx in IHCs, and increased the maximal firing rate of SGNs at sound onset. We propose that IHCs diversify Ca2+ channel properties among AZs and thereby contribute to decomposing auditory information into complementary representations in SGNs

E-NTPDases in human airways: Regulation and relevance for chronic lung diseases

Chronic obstructive lung diseases are characterized by the inability to prevent bacterial infection and a gradual loss of lung function caused by recurrent inflammatory responses. In the past decade, numerous studies have demonstrated the importance of nucleotide-mediated bacterial clearance. Their interaction with P2 receptors on airway epithelia provides a rapid ‘on-and-off’ signal stimulating mucus secretion, cilia beating activity and surface hydration. On the other hand, abnormally high ATP levels resulting from damaged epithelia and bacterial lysis may cause lung edema and exacerbate inflammatory responses. Airway ATP concentrations are regulated by ecto nucleoside triphosphate diphosphohydrolases (E-NTPDases) which are expressed on the mucosal surface and catalyze the sequential dephosphorylation of nucleoside triphosphates to nucleoside monophosphates (ATP → ADP → AMP). The common bacterial product, Pseudomonas aeruginosa lipopolysaccharide (LPS), induces an acute reduction in azide-sensitive E-NTPDase activities, followed by a sustained increase in activity as well as NTPDase 1 and NTPDase 3 expression. Accordingly, chronic lung diseases, including cystic fibrosis (CF) and primary ciliary dyskinesia, are characterized by higher rates of nucleotide elimination, azide-sensitive E-NTPDase activities and expression. This review integrates the biphasic regulation of airway E-NTPDases with the function of purine signaling in lung diseases. During acute insults, a transient reduction in E-NTPDase activities may be beneficial to stimulate ATP-mediated bacterial clearance. In chronic lung diseases, elevating E-NTPDase activities may represent an attempt to prevent P2 receptor desensitization and nucleotide-mediated lung damage

Ca2+-binding protein 2 inhibits Ca2+-channel inactivation in mouse inner hair cells

Ca2+ channels mediate excitation-secretion coupling and show little inactivation at sensory ribbon synapses, enabling reliable synaptic information transfer during sustained stimulation. Studies of Ca2+-channel complexes in HEK293 cells indicated that Ca2+-binding proteins (CaBPs) antagonize their calmodulin-dependent inactivation. Although human mutations affecting CABP2 were shown to cause hearing impairment, the role of CaBP2 in auditory function and the precise disease mechanism remained enigmatic. Here, we disrupted CaBP2 in mice and showed that CaBP2 is required for sound encoding at inner hair cell synapses, likely by suppressing Ca2+-channel inactivation. We propose that the number of activatable Ca2+ channels at the active zone is reduced when CaBP2 is lacking, as is likely the case with the newly described human CABP2 mutation

Clinical pharmacology of exogenously administered alkaline phosphatase

Purpose: To evaluate the clinical pharmacology of exogenous alkaline phosphatase (AP). Methods: Randomized, double-blind, placebo-controlled sequential protocols of (1) ascending doses and infusion duration (volunteers) and (2) fixed dose and duration (patients) were conducted at clinical pharmacology and intensive care units. A total of 103 subjects (67 male volunteers and 36 patients with severe sepsis) were administered exogenous, 10-min IV infusions (three ascending doses) or 24-72 h continuous (132.5-200 U kg-124 h-1) IV infusion with/without preceding loading dose and experimental endotoxemia for evaluations of pharmacokinetics, pharmacodynamics, safety parameters, antigenicity, inflammatory markers, and outcomes. Results: Linearity and dose-proportionality were shown during 10-min infusions. The relatively short elimination half-life necessitated a loading dose to achieve stable enzyme levels. Pharmacokinetic parameters in volunteers and patients were similar. Innate immunity response was not significantly influenced by AP, while renal function significantly improved in sepsis patients. Conclusions: The pharmacokinetics of exogenous AP is linear, dose-proportional, exhibit a short half-life, and are not influenced by renal impairment or dialysis

The synaptic ribbon is critical for sound encoding at high rates and with temporal precision.

We studied the role of the synaptic ribbon for sound encoding at the synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) in mice lacking RIBEYE (RBEKO/KO). Electron and immunofluorescence microscopy revealed a lack of synaptic ribbons and an assembly of several small active zones (AZs) at each synaptic contact. Spontaneous and sound-evoked firing rates of SGNs and their compound action potential were reduced, indicating impaired transmission at ribbonless IHC-SGN synapses. The temporal precision of sound encoding was impaired and the recovery of SGN-firing from adaptation indicated slowed synaptic vesicle (SV) replenishment. Activation of Ca2+-channels was shifted to more depolarized potentials and exocytosis was reduced for weak depolarizations. Presynaptic Ca2+-signals showed a broader spread, compatible with the altered Ca2+-channel clustering observed by super-resolution immunofluorescence microscopy. We postulate that RIBEYE disruption is partially compensated by multi-AZ organization. The remaining synaptic deficit indicates ribbon function in SV-replenishment and Ca2+-channel regulation

The future sea-level rise contribution of Greenland’s glaciers and ice caps

We calculate the future sea-level rise contribution from the surface mass balance of all of Greenland's glaciers and ice caps (GICs, ~90 000 km2) using a simplified energy balance model which is driven by three future climate scenarios from the regional climate models HIRHAM5, RACMO2 and MAR. Glacier extent and surface elevation are modified during the mass balance model runs according to a glacier retreat parameterization. Mass balance and glacier surface change are both calculated on a 250 m resolution digital elevation model yielding a high level of detail and ensuring that important feedback mechanisms are considered. The mass loss of all GICs by 2098 is calculated to be 2016 ± 129 Gt (HIRHAM5 forcing), 2584 ± 109 Gt (RACMO2) and 3907 ± 108 Gt (MAR). This corresponds to a total contribution to sea-level rise of 5.8 ± 0.4, 7.4 ± 0.3 and 11.2 ± 0.3 mm, respectively. Sensitivity experiments suggest that mass loss could be higher by 20–30% if a strong lowering of the surface albedo were to take place in the future. It is shown that the sea-level rise contribution from the north-easterly regions of Greenland is reduced by increasing precipitation while mass loss in the southern half of Greenland is dominated by steadily decreasing summer mass balances. In addition we observe glaciers in the north-eastern part of Greenland changing their characteristics towards greater activity and mass turnover

Amplified melt and flow of the Greenland ice sheet driven by late-summer cyclonic rainfall

Intense rainfall events significantly affect Alpine and Alaskan glaciers through enhanced melting, ice-flow acceleration and subglacial sediment erosion, yet their impact on the Greenland ice sheet has not been assessed. Here we present measurements of ice velocity, subglacial water pressure and meteorological variables from the western margin of the Greenland ice sheet during a week of warm, wet cyclonic weather in late August and early September 2011. We find that extreme surface runoff from melt and rainfall led to a widespread acceleration in ice flow that extended 140 km into the ice-sheet interior. We suggest that the late-season timing was critical in promoting rapid runoff across an extensive bare ice surface that overwhelmed a subglacial hydrological system in transition to a less-efficient winter mode. Reanalysis data reveal that similar cyclonic weather conditions prevailed across southern and western Greenland during this time, and we observe a corresponding ice-flow response at all land- and marine-terminating glaciers in these regions for which data are available. Given that the advection of warm, moist air masses and rainfall over Greenland is expected to become more frequent in the coming decades, our findings portend a previously unforeseen vulnerability of the Greenland ice sheet to climate change