Microlensing Constraints on Broad Absorption and Emission Line Flows in the Quasar H1413+117

We present new integral field spectroscopy of the gravitationally lensed broad absorption line (BAL) quasar H1413+117, covering the ultraviolet to visible rest-frame spectral range. We observe strong microlensing signatures in lensed image D, and we use this microlensing to simultaneously constrain both the broad emission and broad absorption line gas. By modeling the lens system over the range of probable lensing galaxy redshifts and using on a new argument based on the wavelength-independence of the broad line lensing magnifications, we determine that there is no significant broad line emission from smaller than ~20 light days. We also perform spectral decomposition to derive the intrinsic broad emission line (BEL) and continuum spectrum, subject to BAL absorption. We also reconstruct the intrinsic BAL absorption profile, whose features allow us to constrain outflow kinematics in the context of a disk-wind model. We find a very sharp, blueshifted onset of absorption of 1,500 km/s in both C IV and N V that may correspond to an inner edge of a disk-wind's radial outflow. The lower ionization Si IV and Al III have higher-velocity absorption onsets, consistent with a decreasing ionization parameter with radius in an accelerating outflow. There is evidence of strong absorption in the BEL component which indicates a high covering factor for absorption over two orders of magnitude in outflow radius.Comment: 29 pages, 8 figure

A Novel Dopamine Receptor Signaling Unit in Brain: Heterooligomers of D1 And D2 Dopamine Receptors

The ability of G protein coupled receptors to heterooligomerize and create novel signaling complexes has demonstrated the tremendous potential of these receptors to access diverse signaling cascades, as well as to modulate the nature of the transduced signal. In the dopamine receptor field, the existence of a D1-like receptor in brain that activated phospatidylinositol turnover has been shown, but definition of the molecular entity remained elusive. We discovered that the D1 and D2 receptors form a heterooligomer, which on activation of both receptors, coupled to Gq to activate phospholipase C and generate intracellular calcium release. The activation of Gq by the D1-D2 heterooligomer has been shown to occur in cells expressing both receptors, as well as in striatum, distinct from Gs/olf or Gi/o activation by the D1 and D2 receptor homooligomers, respectively. The activation of the D1-D2 receptor heterooligomer in brain led to a calcium signal–mediated increase in phosphorylation of calmodulin kinase lla. The calcium signal rapidly desensitized and the receptors cointernalized after occupancy of either the D1 or D2 binding pocket. Thus, the D1-D2 heterooligomer directly links the action of dopamine to rapid calcium signaling and likely has important effects on dopamine-mediated synaptic plasticity and its functional correlates in brain

Dopamine D1-D2 receptor heteromer signaling pathway in the brain: emerging physiological relevance

Dopamine is an important catecholamine neurotransmitter modulating many physiological functions, and is linked to psychopathology of many diseases such as schizophrenia and drug addiction. Dopamine D1 and D2 receptors are the most abundant dopaminergic receptors in the striatum, and although a clear segregation between the pathways expressing these two receptors has been reported in certain subregions, the presence of D1-D2 receptor heteromers within a unique subset of neurons, forming a novel signaling transducing functional entity has been shown. Recently, significant progress has been made in elucidating the signaling pathways activated by the D1-D2 receptor heteromer and their potential physiological relevance

Activation of WNT and BMP signaling in adult human articular cartilage following mechanical injury

Peer reviewedPublisher PD

The Dopamine D1–D2 Receptor Heteromer in Striatal Medium Spiny Neurons: Evidence for a Third Distinct Neuronal Pathway in Basal Ganglia

Dopaminergic signaling within the basal ganglia has classically been thought to occur within two distinct neuronal pathways; the direct striatonigral pathway which contains the dopamine D1 receptor and the neuropeptides dynorphin (DYN) and substance P, and the indirect striatopallidal pathway which expresses the dopamine D2 receptor and enkephalin (ENK). A number of studies have also shown, however, that D1 and D2 receptors can co-exist within the same medium spiny neuron and emerging evidence indicates that these D1/D2-coexpressing neurons, which also express DYN and ENK, may comprise a third neuronal pathway, with representation in both the striatonigral and striatopallidal projections of the basal ganglia. Furthermore, within these coexpressing neurons it has been shown that the dopamine D1 and D2 receptor can form a novel and pharmacologically distinct receptor complex, the dopamine D1–D2 receptor heteromer, with unique signaling properties. This is indicative of a functionally unique role for these neurons in brain. The aim of this review is to discuss the evidence in support of a novel third pathway coexpressing the D1 and D2 receptor, to discuss the potential relevance of this pathway to basal ganglia signaling, and to address its potential value, and that of the dopamine D1–D2 receptor heteromer, in the search for new therapeutic strategies for disorders involving dopamine neurotransmission

D1 dopamine receptor activity is not altered by a mutation in the first intracellular loop

AbstractThe first intracellular loop of the G protein-coupled receptors (GPCRs) is probably the domain that has been studied least. According to the limited data available, mutations of this region can increase, decrease or not affect receptor-G protein coupling, depending on the receptor. Melanocyte-stimulating hormone (MSH) receptors with a Ser69Leu mutation of the first intracellular loop phenotypically confer tobacco color to the coat of mice, and have constitutive activity and enhanced agonist stimulation of adenylyl cyclase. Since the human D1 dopamine receptor (D1DR) has a serine at the equivalent position, we were interested to see if this serine is involved in receptor-G protein coupling in a similar fashion. Our site-directed mutagenesis study showed that the replacement of this serine by leucine (Ser56Leu) in D1DR did not affect the ability of the receptors to bind ligand or couple to G protein

Dopamine D1–D2 Receptor Heteromer in Dual Phenotype GABA/Glutamate-Coexpressing Striatal Medium Spiny Neurons: Regulation of BDNF, GAD67 and VGLUT1/2

In basal ganglia a significant subset of GABAergic medium spiny neurons (MSNs) coexpress D1 and D2 receptors (D1R and D2R) along with the neuropeptides dynorphin (DYN) and enkephalin (ENK). These coexpressing neurons have been recently shown to have a region-specific distribution throughout the mesolimbic and basal ganglia circuits. While the functional relevance of these MSNs remains relatively unexplored, they have been shown to exhibit the unique property of expressing the dopamine D1–D2 receptor heteromer, a novel receptor complex with distinct pharmacology and cell signaling properties. Here we showed that MSNs coexpressing the D1R and D2R also exhibited a dual GABA/glutamate phenotype. Activation of the D1R–D2R heteromer in these neurons resulted in the simultaneous, but differential regulation of proteins involved in GABA and glutamate production or vesicular uptake in the nucleus accumbens (NAc), ventral tegmental area (VTA), caudate putamen and substantia nigra (SN). Additionally, activation of the D1R–D2R heteromer in NAc shell, but not NAc core, differentially altered protein expression in VTA and SN, regions rich in dopamine cell bodies. The identification of a MSN with dual inhibitory and excitatory intrinsic functions provides new insights into the neuroanatomy of the basal ganglia and demonstrates a novel source of glutamate in this circuit. Furthermore, the demonstration of a dopamine receptor complex with the potential to differentially regulate the expression of proteins directly involved in GABAergic inhibitory or glutamatergic excitatory activation in VTA and SN may potentially provide new insights into the regulation of dopamine neuron activity. This could have broad implications in understanding how dysregulation of neurotransmission within basal ganglia contributes to dopamine neuronal dysfunction

Performance of care for end‐of‐life cancer patients in Tuscany: The interplay between place of care, aggressive treatments, opioids, and place of death. A retrospective cohort study

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