Evidence of G-protein-coupled receptor and substrate transporter heteromerization at a single molecule level

G-protein-coupled receptors (GPCRs) can constitute complexes with non-GPCR integral membrane proteins, while such interaction has not been demonstrated at a single molecule level so far. We here investigated the potential interaction between the thyrotropin receptor (TSHR) and the monocarboxylate transporter 8 (MCT8), a member of the major facilitator superfamily (MFS), using fluorescence cross-correlation spectroscopy (FCCS). Both the proteins are expressed endogenously on the basolateral plasma membrane of the thyrocytes and are involved in stimulation of thyroid hormone production and release. Indeed, we demonstrate strong interaction between both the proteins which causes a suppressed activation of G_q/11 by TSH-stimulated TSHR. Thus, we provide not only evidence for a novel interaction between the TSHR and MCT8, but could also prove this interaction on a single molecule level. Moreover, this interaction forces biased signaling at the TSHR. These results are of general interest for both the GPCR and the MFS research fields.     

Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis

Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10?1?). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10?3). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10?2?, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.     

Centennial-scale climate cooling with a sudden cold event around 8,200 years ago

The extent of climate variability during the current interglacial period, the Holocene, is still debated. Temperature records derived from central Greenland ice cores show one significant temperature anomaly between 8,200 and 8,100 years ago, which is often attributed to a meltwater outflow into the North Atlantic Ocean and a slowdown of North Atlantic Deep Water formation--this anomaly provides an opportunity to study such processes with relevance to present-day freshening of the North Atlantic. Anomalies in climate proxy records from locations around the globe are often correlated with this sharp event in Greenland. But the anomalies in many of these records span 400 to 600 years, start from about 8,600 years ago and form part of a repeating pattern within the Holocene. More sudden climate changes around 8,200 years ago appear superimposed on this longer-term cooling. The compounded nature of the signals implies that far-field climate anomalies around 8,200 years ago cannot be used in a straightforward manner to assess the impact of a slowdown of North Atlantic Deep Water formation, and the geographical extent of the rapid cooling event 8,200 years ago remains to be determined.     

Reversal of pathological pain through specific spinal GABAA receptor subtypes

Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology. Facilitation of spinal gamma-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABA(A) receptors should be able to compensate for this loss. With the use of GABA(A)-receptor point-mutated knock-in mice in which specific GABA(A) receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA(A) receptors containing the alpha2 and/or alpha3 subunits. We show that their selective activation by the non-sedative ('alpha1-sparing') benzodiazepine-site ligand L-838,417 (ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics.     

Rapid developmental switch in the mechanisms driving early cortical columnar networks

The immature cerebral cortex self-organizes into local neuronal clusters long before it is activated by patterned sensory inputs. In the cortical anlage of newborn mammals, neurons coassemble through electrical or chemical synapses either spontaneously or by activation of transmitter-gated receptors. The neuronal network and the cellular mechanisms underlying this cortical self-organization process during early development are not completely understood. Here we show in an intact in vitro preparation of the immature mouse cerebral cortex that neurons are functionally coupled in local clusters by means of propagating network oscillations in the beta frequency range. In the newborn mouse, this activity requires an intact subplate and is strongly synchronized within a cortical column by gap junctions. With the developmental disappearance of the subplate at the end of the first postnatal week, activation of NMDA (N-methyl-D-aspartate) receptors in the immature cortical network is essential to generate this columnar activity pattern. Our findings show that during a brief developmental period the cortical network switches from a subplate-driven, gap-junction-coupled syncytium to a synaptic network acting through NMDA receptors to generate synchronized oscillatory activity, which may function as an early functional template for the development of the cortical columnar architecture.     

United Kingdom: The Science and Engineering Research Council (SERC): A Report on Research in the United Kingdom,France and Germany (W)

Science Policy News

United Kingdom: The Science and Engineering Research Council (SERC): A Report on Research in the United Kingdom, France and Germany (W)     

Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis

Following up on recent genome-wide association studies (GWAS) of Crohn's disease, we investigated 50 previously reported susceptibility loci in a German sample of individuals with Crohn's disease (n = 1,850) or ulcerative colitis (n = 1,103) and healthy controls (n = 1,817). Among these loci, we identified variants in 3p21.31, NKX2-3 and CCNY as susceptibility factors for both diseases, whereas variants in PTPN2, HERC2 and STAT3 were associated only with ulcerative colitis in our sample collection.     

Chymotrypsin C (CTRC) variants that diminish activity or secretion are associated with chronic pancreatitis

Chronic pancreatitis is a persistent inflammatory disease of the pancreas, in which the digestive protease trypsin has a fundamental pathogenetic role. Here we have analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group, being present in 30 of 901 (3.3%) affected individuals but only 21 of 2,804 (0.7%) controls (odds ratio (OR) = 4.6; confidence interval (CI) = 2.6-8.0; P = 1.3 x 10(-7)). A replication study identified these two variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 432 (0.7%) subjects with alcoholic liver disease (OR = 4.2; CI = 1.2-15.5; P = 0.02). CTRC variants were also found in 10 of 71 (14.1%) Indian subjects with tropical pancreatitis but only 1 of 84 (1.2%) healthy controls (OR = 13.6; CI = 1.7-109.2; P = 0.0028). Functional analysis of the CTRC variants showed impaired activity and/or reduced secretion. The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity.     

Eocene global warming events driven by ventilation of oceanic dissolved organic carbon

'Hyperthermals' are intervals of rapid, pronounced global warming known from six episodes within the Palaeocene and Eocene epochs (～65-34 million years (Myr) ago). The most extreme hyperthermal was the ～170 thousand year (kyr) interval of 5-7 °C global warming during the Palaeocene-Eocene Thermal Maximum (PETM, 56?Myr ago). The PETM is widely attributed to massive release of greenhouse gases from buried sedimentary carbon reservoirs, and other, comparatively modest, hyperthermals have also been linked to the release of sedimentary carbon. Here we show, using new 2.4-Myr-long Eocene deep ocean records, that the comparatively modest hyperthermals are much more numerous than previously documented, paced by the eccentricity of Earth's orbit and have shorter durations (～40?kyr) and more rapid recovery phases than the PETM. These findings point to the operation of fundamentally different forcing and feedback mechanisms than for the PETM, involving redistribution of carbon among Earth's readily exchangeable surface reservoirs rather than carbon exhumation from, and subsequent burial back into, the sedimentary reservoir. Specifically, we interpret our records to indicate repeated, large-scale releases of dissolved organic carbon (at least 1,600 gigatonnes) from the ocean by ventilation (strengthened oxidation) of the ocean interior. The rapid recovery of the carbon cycle following each Eocene hyperthermal strongly suggests that carbon was re-sequestered by the ocean, rather than the much slower process of silicate rock weathering proposed for the PETM. Our findings suggest that these pronounced climate warming events were driven not by repeated releases of carbon from buried sedimentary sources, but, rather, by patterns of surficial carbon redistribution familiar from younger intervals of Earth history.