G protein-coupled receptors (GPCRs) are the largest class of receptors in the human genome and some of the most common drug targets. It is now well established that GPCRs can signal through multiple transducers, including heterotrimeric G proteins, GPCR kinases and β-arrestins. While these signalling pathways can be activated or blocked by 'balanced' agonists or antagonists, they can also be selectively activated in a 'biased' response. Biased responses can be induced by biased ligands, biased receptors or system bias, any of which can result in preferential signalling through G proteins or β-arrestins. At many GPCRs, signalling events mediated by G proteins and β-arrestins have been shown to have distinct biochemical and physiological actions from one another, and an accurate evaluation of biased signalling from pharmacology through physiology is crucial for preclinical drug development. Recent structural studies have provided snapshots of GPCR-transducer complexes, which should aid in the structure-based design of novel biased therapies. Our understanding of GPCRs has evolved from that of two-state, on-and-off switches to that of multistate allosteric microprocessors, in which biased ligands transmit distinct structural information that is processed into distinct biological outputs. The development of biased ligands as therapeutics heralds an era of increased drug efficacy with reduced drug side effects.

Although nitrogen-containing organic compounds (NOC) are important components of atmospheric aerosols, little is known about their chemical composition. Here we present detailed characterization of the NOC constituents of biomass burning aerosol (BBA) samples using high-resolution electrospray ionization mass spectrometry (ESI/MS). Accurate mass measurements combined with MS/MS fragmentation experiments of selected ions were used to assign molecular structures to individual NOC species. Our results indicate that N-heterocyclic alkaloid compounds (species naturally produced by plants and living organisms) comprise a substantial fraction of NOC in BBA samples collected from test burns of five biomass fuels. High abundance of alkaloids in test burns of ponderosa pine (a widespread tree in the western U.S. areas frequently affected by large scale fires) suggests that N-heterocyclic alkaloids in BBA may play a significant role in dry and wet deposition of fixed nitrogen in this region.

Stressors motivate an array of adaptive responses ranging from “fight or flight” to an internal urgency signal facilitating long-term goals1. However, traumatic or chronic uncontrollable stress promotes the onset of Major Depressive Disorder where acute stressors lose their motivational properties and are perceived as insurmountable impediments2. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal3. An emerging neurobiological substrate of depression and associated pathology is the nucleus accumbens, a region with the capacity to mediate a diverse range of stress responses by interfacing limbic, cognitive and motor circuitry4. Here we report that corticotropin releasing factor (CRF), a neuropeptide released in response to acute stressors5 and other arousing environmental stimuli6, acts in the nucleus accumbens of naïve mice to increase dopamine release through co-activation of CRF R1 and R2 receptors. Remarkably, severe stress exposure completely abolished this effect without recovery for at least 90 days. This loss of CRF’s capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors. Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.