Trafficking and signaling of G protein-coupled receptors in the nervous system: implications for disease and therapy

G protein-coupled receptors (GPCRs) are expressed throughout the nervous system where they regulate multiple physiological processes, participate in neurological diseases, and are major targets for therapy. Given that many GPCRs respond to neurotransmitters and hormones that are present in the extracellular fluid and which do not readily cross the plasma membrane, receptor trafficking to and from the plasma membrane is a critically important determinant of cellular responsiveness. Moreover, trafficking of GPCRs throughout the endosomal system can initiate signaling events that are mechanistically and functionally distinct from those operating at the plasma membrane. This review discusses recent advances in the relationship between signaling and trafficking of GPCRs in the nervous system. It summarizes how receptor modifications influence trafficking, discusses mechanisms that regulate GPCR trafficking to and from the plasma membrane, reviews the relationship between trafficking and signaling, and considers the implications of GPCR trafficking to drug development.

p90 ribosomal S6 kinases play a significant role in early gene regulation in the cardiomyocyte response to Gq protein-coupled receptor stimuli, endothelin-1 and α1-adrenergic receptor agonists

Extracellular signal-regulated kinases 1/2 (ERK1/2) and their substrates, p90 ribosomal S6 kinases (RSKs), phosphorylate different transcription factors, contributing differentially to transcriptomic profiles. In cardiomyocytes, ERK1/2 are required for >70% of the transcriptomic response to endothelin-1. Here, we investigated the role of RSKs in the transcriptomic responses to Gq protein-coupled receptor agonists, endothelin-1, phenylephrine (generic α1-adrenergic receptor agonist) and A61603 (α1A-adrenergic receptor selective). Phospho-ERK1/2 and phospho-RSKs appeared in cardiomyocyte nuclei within 2-3 min of stimulation (endothelin-1>a61603≈phenylephrine). All agonists increased nuclear RSK2, but only endothelin-1 increased nuclear RSK1 content. PD184352 (inhibits ERK1/2 activation) and BI-D1870 (inhibits RSKs) were used to dissect the contribution of RSKs to the endothelin-1-responsive transcriptome. Of 213 RNAs upregulated at 1 h, 51% required RSKs for upregulation whereas 29% required ERK1/2 but not RSKs. The transcriptomic response to phenylephrine overlapped with, but was not identical to, endothelin-1. As with endothelin-1, PD184352 inhibited upregulation of most phenylephrine-responsive transcripts, but the greater variation in effects of BI-D1870 suggests that differential RSK signalling influences global gene expression. A61603 induced similar changes in RNA expression in cardiomyocytes as phenylephrine, indicating that the signal was mediated largely through α1A-adrenergic receptors. A61603 also increased expression of immediate early genes in perfused adult rat hearts and, as in cardiomyocytes, upregulation of the majority of genes was inhibited by PD184352. PD184352 or BI-D1870 prevented the increased surface area induced by endothelin-1 in cardiomyocytes. Thus, RSKs play a significant role in regulating cardiomyocyte gene expression and hypertrophy in response to Gq protein-coupled receptor stimulation.

Simulated variations in atmospheric CO2 over a Wisconsin forest using a coupled ecosystem-atmosphere model

Ecosystem fluxes of energy, water, and CO2 result in spatial and temporal variations in atmospheric properties. In principle, these variations can be used to quantify the fluxes through inverse modelling of atmospheric transport, and can improve the understanding of processes and falsifiability of models. We investigated the influence of ecosystem fluxes on atmospheric CO2 in the vicinity of the WLEF-TV tower in Wisconsin using an ecophysiological model (Simple Biosphere, SiB2) coupled to an atmospheric model (Regional Atmospheric Modelling System). Model parameters were specified from satellite imagery and soil texture data. In a companion paper, simulated fluxes in the immediate tower vicinity have been compared to eddy covariance fluxes measured at the tower, with meteorology specified from tower sensors. Results were encouraging with respect to the ability of the model to capture observed diurnal cycles of fluxes. Here, the effects of fluxes in the tower footprint were also investigated by coupling SiB2 to a high-resolution atmospheric simulation, so that the model physiology could affect the meteorological environment. These experiments were successful in reproducing observed fluxes and concentration gradients during the day and at night, but revealed problems during transitions at sunrise and sunset that appear to be related to the canopy radiation parameterization in SiB2.

Secular trends in daily precipitation characteristics: greenhouse gas simulation with a coupled AOGCM

Secular trends of daily precipitation characteristics are considered in the transient climate change experiment with a coupled atmosphere-ocean general circulation model ECHAM4/OPYC3 for 1900-2099. The climate forcing is due to increasing concentrations of the greenhouse gases in the atmosphere. Mean daily precipitation, precipitation intensity, probability of wet days and parameters of the gamma distribution are analyzed. Particular attention is paid to the changes of heavy precipitation, Analysis of the annual mean precipitation trends for 1900-1999 revealed general agreement with observations with significant positive trends in mean precipitation over continental areas. In the 2000-2099 period precipitation trend patterns followed the tendency obtained for 1900-1999 but with significantly increased magnitudes. Unlike the annual mean precipitation trends for which negative values were found for some continental areas, the mean precipitation intensity and scale parameter of the fitted gamma distribution increased over all land territories . Negative trends in the number of wet days were found over most of the land areas except high latitudes in the Northern Hemisphere. The shape parameter of the gamma distribution in general revealed a slight negative trend in the areas of the precipitation increase. Investigation of daily precipitation revealed an unproportional increase of heavy precipitation events for the land areas including local maxima in Europe and the eastern United States.

Intensified Asian summer monsoon and its variability in a coupled model forced by increasing greenhouse gas concentrations

The Asian summer monsoon response to global warming is investigated by a transient green-house warming integration with the ECHAM4/OPYC3 CGCM. It is demonstrated that increases of greenhouse gas concentrations intensify the Asian summer monsoon and its variability. The intensified monsoon results mainly from an enhanced land-sea contrast and a northward shift of the convergence zone. A gradual increase of the monsoon variability is simulated from year 2030 onwards. It seems to be connected with the corresponding increase of the sea surface temperature variability over the tropical Pacific.

Transient climate change simulations with a coupled atmosphere–ocean GCM including the tropospheric sulfur cycle

The time-dependent climate response to changing concentrations of greenhouse gases and sulfate aerosols is studied using a coupled general circulation model of the atmosphere and the ocean (ECHAM4/OPYC3). The concentrations of the well-mixed greenhouse gases like CO2, CH4, N2O, and CFCs are prescribed for the past (1860–1990) and projected into the future according to International Panel on Climate Change (IPCC) scenario IS92a. In addition, the space–time distribution of tropospheric ozone is prescribed, and the tropospheric sulfur cycle is calculated within the coupled model using sulfur emissions of the past and projected into the future (IS92a). The radiative impact of the aerosols is considered via both the direct and the indirect (i.e., through cloud albedo) effect. It is shown that the simulated trend in sulfate deposition since the end of the last century is broadly consistent with ice core measurements, and the calculated radiative forcings from preindustrial to present time are within the uncertainty range estimated by IPCC. Three climate perturbation experiments are performed, applying different forcing mechanisms, and the results are compared with those obtained from a 300-yr unforced control experiment. As in previous experiments, the climate response is similar, but weaker, if aerosol effects are included in addition to greenhouse gases. One notable difference to previous experiments is that the strength of the Indian summer monsoon is not fundamentally affected by the inclusion of aerosol effects. Although the monsoon is damped compared to a greenhouse gas only experiment, it is still more vigorous than in the control experiment. This different behavior, compared to previous studies, is the result of the different land–sea distribution of aerosol forcing. Somewhat unexpected, the intensity of the global hydrological cycle becomes weaker in a warmer climate if both direct and indirect aerosol effects are included in addition to the greenhouse gases. This can be related to anomalous net radiative cooling of the earth’s surface through aerosols, which is balanced by reduced turbulent transfer of both sensible and latent heat from the surface to the atmosphere.

Climatology and variability in the ECHO coupled GCM

ECHO is a new global coupled ocean-atmosphere general circulation model (GCM), consisting of the Hamburg version of the European Centre atmospheric GCM (ECHAM) and the Hamburg Primitive Equation ocean GCM (HOPE). We performed a 20-year integration with ECHO. Climate drift is significant, but typical annual mean errors in sea surface temperature (SST) do not exceed 2° in the open oceans. Near the boundaries, however, SST errors are considerably larger. The coupled model simulates an irregular ENSO cycle in the tropical Pacific, with spatial patterns similar to those observed. The variability, however, is somewhat weaker relative to observations. ECHO also simulates significant interannual variability in mid-latitudes. Consistent with observations, variability over the North Pacific can be partly attributed to remote forcing from the tropics. In contrast, the interannual variability over the North Atlantic appears to be generated locally.

Impact of global warming on the interannual and interdecadal climate modes in a coupled GCM

In this study, we investigated the impact of global warming on the variabilities of large-scale interannual and interdecadal climate modes and teleconnection patterns with two long-term integrations of the coupled general circulation model of ECHAM4/OPYC3 at the Max-Planck-Institute for Meteorology, Hamburg. One is the control (CTRL) run with fixed present-day concentrations of greenhouse gases. The other experiment is a simulation of transient greenhouse warming, named GHG run. In the GHG run the averaged geopotential height at 500 hPa is increased significantly, and a negative phase of the Pacific/North American (PNA) teleconnection-like distribution pattern is intensified. The standard deviation over the tropics (high latitudes) is enhanced (reduced) on the interdecadal time scales and reduced (enhanced) on the interannual time scales in the GHG run. Except for an interdecadal mode related to the Southern Oscillation (SO) in the GHG run, the spatial variation patterns are similar for different (interannual + interdecadal, interannual, and interdecadal) time scales in the GHG and CTRL runs. Spatial distributions of the teleconnection patterns on the interannual and interdecadal time scales in the GHG run are also similar to those in the CTRL run. But some teleconnection patterns show linear trends and changes of variances and frequencies in the GHG run. Apart from the positive linear trend of the SO, the interdecadal modulation to the El Niño/SO cycle is enhanced during the GHG 2040 ∼ 2099. This is the result of an enhancement of the Walker circulation during that period. La Niña events intensify and El Niño events relatively weaken during the GHG 2070 ∼ 2090. It is interesting to note that with increasing greenhouse gas concentrations the relation between the SO and the PNA pattern is reversed significantly from a negative to a positive correlation on the interdecadal time scales and weakened on the interannual time scales. This suggests that the increase of the greenhouse gas concentrations will trigger the nonstationary correlation between the SO and the PNA pattern both on the interdecadal and interannual time scales.

Impact of global warming on the Asian winter monsoon in a coupled GCM

The Asian winter monsoon (AWM) response to the global warming was investigated through a long-term integration of the transient greenhouse warming with the ECHAM4/OPYC3 CGCM. The physics of the response was studied through analyses of the impact of the global warming on the variations of the ocean and land contrast near the ground in the Asian and western Pacific region and the east Asian trough and jet stream in the middle and upper troposphere. Forcing of transient eddy activity on the zonal circulation over the Asian and western Pacific region was also analyzed. It is found that in the global warming scenario the winter northeasterlies along the Pacific coast of the Eurasian continent weaken systematically and significantly, and intensity of the AWM reduces evidently, but the AWM variances on the interannual and interdecadal scales are not affected much by the global warming. It is suggested that the global warming makes the climate over the most part of Asia to be milder with enhanced moisture in winter. In the global warming scenario the contrasts of the sea level pressure and the near-surface temperature between the Asian continent and the Pacific Ocean become significantly smaller, northward and eastward shifts and weakening of the east Asian trough and jet stream in the middle and upper troposphere are found. As a consequence, the cold air in the AWM originating from the east Asian trough and high latitudes is less powerful. In addition, feedback of the transient activity also makes a considerable contribution to the higher-latitude shift of the jet stream over the North Pacific in the global warming scenario.

A strategy for process-oriented validation of coupled chemistry–climate models

Evaluating CCMs with the presented framework will increase our confidence in predictions of stratospheric ozone change.

Coupled Kelvin-wave and mirage-wave instabilities in semigeostrophic dynamics

A weak instability mode, associated with phase-locked counterpropagating coastal Kelvin waves in horizontal anticyclonic shear, is found in the semigeostrophic (SG) equations for stratified flow in a channel. This SG instability mode approximates a similar mode found in the Euler equations in the limit in which particle-trajectory slopes are much smaller than f/N, where f is the Coriolis frequency and N > f the buoyancy frequency. Though weak under normal parameter conditions, this instability mode is of theoretical interest because its existence accounts for the failure of an Arnol’d-type stability theorem for the SG equations. In the opposite limit, in which the particle motion is purely vertical, the Euler equations allow only buoyancy oscillations with no horizontal coupling. The SG equations, on the other hand, allow a physically spurious coastal “mirage wave,” so called because its velocity field vanishes despite a nonvanishing disturbance pressure field. Counterpropagating pairs of these waves can phase-lock to form a spurious “mirage-wave instability.” Closer examination shows that the mirage wave arises from failure of the SG approximations to be self-consistent for trajectory slopes f/N.

Response of tropical cyclones to idealized climate change experiments in a global high resolution coupled general circulation model

We present an assessment of how tropical cyclone activity might change due to the influence of increased atmospheric carbon dioxide concentrations, using the UK’s High Resolution Global Environment Model (HiGEM) with N144 resolution (~90 km in the atmosphere and ~40 km in the ocean). Tropical cyclones are identified using a feature tracking algorithm applied to model output. Tropical cyclones from idealized 30-year 2×CO2 (2CO2) and 4×CO2 (4CO2) simulations are compared to those identified in a 150-year present-day simulation, which is separated into a 5-member ensemble of 30-year integrations. Tropical cyclones are shown to decrease in frequency globally by 9% in the 2CO2 and 26% in the 4CO2. Tropical cyclones only become more intese in the 4CO2, however uncoupled time slice experiments reveal an increase in intensity in the 2CO2. An investigation into the large-scale environmental conditions, known to influence tropical cyclone activity in the main development regions, is used to determine the response of tropical cyclone activity to increased atmospheric CO2. A weaker Walker circulation and a reduction in zonally averaged regions of updrafts lead to a shift in the location of tropical cyclones in the northern hemisphere. A decrease in mean ascent at 500 hPa contributes to the reduction of tropical cyclones in the 2CO2 in most basins. The larger reduction of tropical cyclones in the 4CO2 arises from further reduction of mean ascent at 500 hPa and a large enhancement of vertical wind shear, especially in the southern hemisphere, North Atlantic and North East Pacific.

Analysis of precipitation climatology simulated by high resolution coupled global models over the South America

The results of coupled high resolution global models (CGCMs) over South America are discussed. HiGEM1.2 and HadGEM1.2 simulations, with horizontal resolution of ~90 and 135 km, respectively, are compared. Precipitation estimations from CMAP (Climate Prediction Center—Merged Analysis of Precipitation), CPC (Climate Prediction Center) and GPCP (Global Precipitation Climatology Project) are used for validation. HiGEM1.2 and HadGEM1.2 simulated seasonal mean precipitation spatial patterns similar to the CMAP. The positioning and migration of the Intertropical Convergence Zone and of the Pacific and Atlantic subtropical highs are correctly simulated by the models. In HiGEM1.2 and HadGEM1.2, the intensity and locations of the South Atlantic Convergence Zone are in agreement with the observed dataset. The simulated annual cycles are in phase with estimations of rainfall for most of the six regions considered. An important result is that HiGEM1.2 and HadGEM1.2 eliminate a common problem of coarse resolution CGCMs, which is the simulation of a semiannual cycle of precipitation due to the semiannual solar forcing. Comparatively, the use of high resolution in HiGEM1.2 reduces the dry biases in the central part of Brazil during austral winter and spring and in most part of the year over an oceanic box in eastern Uruguay.