Dopamine and endogenous cannabinoids display complex interactions in the basal ganglia. One possible level of interaction is between CB1 cannabinoid and D2 dopamine receptors. Here, we demonstrate that a regulated association of CB1 and D2 receptors profoundly alters CB1 signaling. This provides the first evidence that CB1/D2 receptor complexes exist, are dynamic, and are agonist-regulated with highest complex levels detected when both receptors are stimulated with subsaturating concentrations of agonist. The consequence of this interaction is a differential preference for signaling through a "nonpreferred" G protein. In this case, D2 receptor activation, simultaneously with CB1 receptor stimulation, results in the receptor complex coupling to G␣s protein in preference to the expected G␣i/o proteins. The result of this interaction is an increase in the second messenger cAMP, reversing an initial synergistic inhibition of adenylyl cyclase activity seen at subthreshold concentrations of cannabinoid agonist. Additionally, a pertussis toxin insensitive component in the activation of extracellular signal-regulated kinase (ERK) 1/2 kinases by the cannabinoid agonist CP 55,940 [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol] is revealed in cells stably expressing both CB1 and D2 receptors. Thus, concurrent receptor stimulation promotes a heterooligomeric receptor complex and an apparent shift of CB1 signaling from a pertussis toxin-sensitive inhibition to a partly pertussis toxin-insensitive stimulation of adenylyl cyclase and ERK 1/2 phosphorylation.
Genome sequencing projects have focused attention on the problem of discovering the functions of protein domains that are widely distributed throughout living species but which are, as yet, largely uncharacterized. One such example is the PIN domain, found in eukaryotes, bacteria, and Archaea, and with suggested roles in signaling, RNase editing, and/or nucleotide binding. The first reported crystal structure of a PIN domain (open reading frame PAE2754, derived from the crenarchaeon, Pyrobaculum aerophilum) has been determined to 2.5 Å resolution and is presented here. Mapping conserved residues from a multiple sequence alignment onto the structure identifies a putative active site. The discovery of distant structural homology with several exonucleases, including T4 phage RNase H and flap endonuclease (FEN1), further suggests a likely function for PIN domains as Mg 2؉ -dependent exonucleases, a hypothesis that we have confirmed in vitro. The tetrameric structure of PAE2754, with the active sites inside a tunnel, suggests a mechanism for selective cleavage of single-stranded overhangs or flap structures. These results indicate likely DNA or RNA editing roles for prokaryotic PIN domains, which are strikingly numerous in thermophiles, and in organisms such as Mycobacterium tuberculosis. They also support previous hypotheses that eukaryotic PIN domains participate in RNA i and nonsense-mediated RNA degradation.The explosive growth of whole genome sequencing efforts, and the discovery that a large proportion of the assumed gene products are of unknown or poorly understood function, has focused attention on new approaches to assigning function. In the absence of sufficient sequence similarity to clearly infer homology with already characterized proteins, a variety of bioinformatic approaches have been used to obtain functional clues. These include, for example, analyses of genome location (seeking potential operons), phylogenetic profiling, and observations of gene fusions in different species (1, 2). An alternative, complementary, approach is to use analyses of protein three-dimensional structure to derive functional insights, because three-dimensional structure is conserved in evolution much more strongly than sequence. This provides a rationale for a number of structural genomics initiatives (3-6).As part of a pilot structural genomics project aimed at the discovery of biological function, we have focused on gene products from the hyperthermophilic crenarchaeon Pyrobaculum aerophilum, an organism whose complete genome sequence was published recently (7). A whole-genome comparison of P. aerophilum and Mycobacterium tuberculosis, two organisms with very different, and in a sense extreme, lifestyles, led us to identify a set of 250 pairs of orthologous genes that are both widely distributed in nature and are shared by these two organisms. Among these were a set of four genes from P. aerophilum (PAE0151, PAE0285, PAE0337, and PAE2754) and four from M. tuberculosis (Rv0065, Rv0549, Rv0960, and Rv1720) that have since be...
The decision was presented as an ongoing process by the mothers, their concerns representing their desire to do their best as parents for their children. Theoretically, the mothers' description of the process can be understood in terms of their attempts to resolve an ethical dilemma. Clinical implications include recognition of the role of the psychologist in supporting mothers in their decision making and thus indirectly helping children.
A plethora of programmes for improving delivery for social 'need' through customer involvement, voice and choice have hit the housing, care and support sector over the last ten years at an ever-increasing pace. Providers of these welfare services are faced with pressure to compete via often aggressive procurement processes, and now in marketing their services direct to the consumer via direct payments and individual budgets.This free market economy approach to the provision of services which people need rather than want is a cultural challenge for the non-profit sector, and one which many feel as a conflict with their ethos and values. That isn't to say that providers are against service user involvement, and excellent practice exists at all levels in the provision process, from setting priorities and strategy for commissioning, involvement in commissioning, procurement and review of service providers, to operational management on provider management boards and service meetings. The nonprofit sector has recognised, if gradually at first, that the best way of buying and delivering services which actually deliver the outcomes is to ask and involve the experts -those who use or have used the services.Consumerism and free market economics in the provision of welfare services, whether these are 'safety net' or 'preventative' 30Housing, care and support 9.
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