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Wonjo Jang C. Elizabeth Adams Heng Liu Cheng Zhang Finn Olav Levy Kjetil Wessel Andressen Nevin A. Lambert 《Proceedings of the National Academy of Sciences of the United States of America》2020,117(48):30755
Agonist binding promotes activation of G protein-coupled receptors (GPCRs) and association of active receptors with G protein heterotrimers. The resulting active-state ternary complex is the basis for conventional stimulus-response coupling. Although GPCRs can also associate with G proteins before agonist binding, the impact of such preassociated complexes on agonist-induced signaling is poorly understood. Here we show that preassociation of 5-HT7 serotonin receptors with Gs heterotrimers is necessary for agonist-induced signaling. 5-HT7 receptors in their inactive state associate with Gs, as these complexes are stabilized by inverse agonists and receptor mutations that favor the inactive state. Inactive-state 5-HT7–Gs complexes dissociate in response to agonists, allowing the formation of conventional agonist–5-HT7–Gs ternary complexes and subsequent Gs activation. Inactive-state 5-HT7–Gs complexes are required for the full dynamic range of agonist-induced signaling, as 5-HT7 receptors spontaneously activate Gs variants that cannot form inactive-state complexes. Therefore, agonist-induced signaling in this system involves two distinct receptor-G protein complexes, a conventional ternary complex that activates G proteins and an inverse-coupled binary complex that maintains the inactive state when agonist is not present.G protein-coupled receptors (GPCRs) transduce a wide variety of physiological signals and are targeted by a substantial fraction of all therapeutic drugs (1). GPCRs are conformationally dynamic and transition between inactive and active states, the latter being capable of interacting with and activating heterotrimeric G proteins (2). Although some level of constitutive activity is common, the conformational equilibrium “setpoint” usually favors the inactive state of the receptor, thus keeping the system turned off and ready to respond to agonists. Agonist binding stabilizes active conformations and promotes the formation of transient active-state ternary agonist-receptor-G protein complexes (3). This positive allosteric interaction between agonist and G protein binding is the hallmark of conventional GPCR coupling. Receptor-G protein complexes that form before agonist binding have also been described (4–8) and are generally thought of as a means to promote rapid or specific signaling after agonist binding. However, the properties and functional significance of such “preassociated” complexes are largely unknown, and inactive receptor conformations are generally considered unable to interact with G proteins. Here we show that unliganded 5-HT7 serotonin receptors form complexes with Gs heterotrimers, and that these complexes help maintain the receptor in an inactive state. Agonist binding leads to dissociation of inactive-state 5-HT7–Gs complexes, which in turn allows increased formation of active-state 5-HT7–Gs complexes and G protein activation. Thus, a negative allosteric interaction between agonist and G protein binding is required for the full sensitivity of these receptors to serotonin. 相似文献
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Maagaard A Holberg-Petersen M Løvgården G Holm M Pettersen FO Kvale D 《The Journal of infectious diseases》2008,198(10):1474-1481
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Basolateral membrane targeting of a renal-epithelial inwardly rectifying potassium channel from the cortical collecting duct, CCD-IRK3, in MDCK cells 下载免费PDF全文
Sophie Le Maout Manuel Brejon Olav Olsen Jean Merot Paul A. Welling 《Proceedings of the National Academy of Sciences of the United States of America》1997,94(24):13329-13334
We recently cloned an inward-rectifying K channel (Kir) cDNA, CCD-IRK3 (mKir 2.3), from a cortical collecting duct (CCD) cell line. Although this recombinant channel shares many functional properties with the “small-conductance” basolateral membrane Kir channel in the CCD, its precise subcellular localization has been difficult to elucidate by conventional immunocytochemistry. To circumvent this problem, we studied the targeting of several different epitope-tagged CCD-IRK3 in a polarized renal epithelial cell line. Either the 11-amino acid span of the vesicular stomatitis virus (VSV) G glycoprotein (P5D4 epitope) or a 6-amino acid epitope of the bovine papilloma virus capsid protein (AU1) was genetically engineered on the extreme N terminus of CCD-IRK3. As determined by patch-clamp and two-microelectrode voltage-clamp analyses in Xenopus oocytes, neither tag affected channel function; no differences in cation selectivity, barium block, single channel conductance, or open probability could be distinguished between the wild-type and the tagged constructs. MDCK cells were transfected with tagged CCD-IRK3, and several stable clonal cell lines were generated by neomycin-resistance selection. Immunoprecipitation studies with anti-P5D4 or anti-AU1 antibodies readily detected the predicted-size 50-kDa protein in the transfected cells lines but not in wild-type or vector-only (PcB6) transfected MDCK cells. As visualized by indirect immunofluorescence and confocal microscopy, both the tagged CCD-IRK3 forms were exclusively detected on the basolateral membrane. To assure that the VSV G tag was not responsible for the targeting, the P5D4 epitope modified by a site-directed mutagenesis (Y2F) to remove a potential basolateral targeting signal contained in this tag. VSV(Y2F) was also detected exclusively on the basolateral membrane, confirming bona fide IRK3 basolateral expression. These observations, with our functional studies, suggest that CCD-IRK3 may encode the small-conductance CCD basolateral K channel. 相似文献
45.
Dora M. Dumont Christopher Wildeman Hedwig Lee Annie Gjelsvik Pamela Valera Jennifer G. Clarke 《Maternal and child health journal》2014,18(9):2179-2187
Parental incarceration is associated with mental and physical health problems in children, yet little research directly tests mechanisms through which parental incarceration could imperil child health. We hypothesized that the incarceration of a woman or her romantic partner in the year before birth constituted an additional hardship for already-disadvantaged women, and that these additionally vulnerable women were less likely to engage in positive perinatal health behaviors important to infant and early childhood development. We analyzed 2006–2010 data from the Pregnancy Risk Assessment and Monitoring System to assess the association between incarceration in the year prior to the birth of a child and perinatal maternal hardships and behaviors. Women reporting incarceration of themselves or their partners in the year before birth of a child had .86 the odds (95 % CI .78–.95) of beginning prenatal care in the first trimester compared to women not reporting incarceration. They were nearly twice as likely to report partner abuse and were significantly more likely to rely on WIC and/or Medicaid for assistance during pregnancy. These associations persist after controlling for socioeconomic measures and other stressors, including homelessness and job loss. Incarceration of a woman or her partner in the year before birth is associated with higher odds of maternal hardship and poorer perinatal health behaviors. The unprecedented scale of incarceration in the US simultaneously presents an underutilized public health opportunity and constitutes a social determinant of health that may contribute to disparities in early childhood development. 相似文献
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Aron Adelved Anna T?tterman Johan C Hellund Thomas Glott Jan Erik Madsen Olav R?ise 《Acta orthopaedica》2014,85(4):408-414
Background and purpose
Neurological deficits and pain are common after displaced sacral fractures. However, little is known about the association between the long-term clinical outcomes and radiological findings. We examined the long-term radiological findings and their correlations with lumbosacral pain and neurological deficits in the lower extremities after surgery for sacral fractures.Methods
28 consecutive patients with operatively treated displaced sacral fractures were followed for mean 11 (8–13) years. Sensorimotor impairments of the lower extremities were classified according to the American Spinal Injury Association (ASIA). Pain was assessed using a visual analog scale (VAS). All patients underwent conventional radiographic examination and CT, and the images were scrutinized for nonunion, residual displacement, narrowing of the sacral foramina, and post-foraminal encroachment of the L5 and S1 nerves.Results
There was residual displacement of ≥ 10 mm in 16 of the 28 patients. 26 patients had narrowing of 1 or more neural root foramina in L5-S4. 8 patients reported having no pain, 11 had pain only in the lumbosacral area, and 9 had pain in combination with radiating leg pain. Statistically significant correlations were found between narrowing of the sacral foramina and neurological deficits in the corresponding dermatomes. Significant correlations were also found between post-foraminal encroachment of L5 nerves and both sensory and motor deficits. No correlations were found between pain and radiological findings.Interpretation
Pathological radiological findings are common 11 years after operatively treated displaced sacral fractures. Sacral foraminal and L5 post-foraminal bony encroachments were common findings and correlated with neurological deficits. However, lumbosacral pain did not correlate with radiological sequelae after fracture healing.High-energy trauma with displaced sacral fracture is frequently associated with concomitant injuries to the intrapelvic soft tissue structures, including the lumbosacral plexus (Huittinen 1972, Denis et al. 1988, Majeed 1992). These injuries may cause considerable morbidity (Pohlemann et al. 1994, Tornetta and Matta 1996, Tötterman et al. 2006). However, little is known about which factors determine long-term clinical outcome in these patients, or what may explain the progression of neurological symptoms observed in a small proportion of patients (Adelved et al. 2012). Pelvic malunions and nonunions have been put forward as prognostic factors for impaired long-term outcome (Matta et al. 1996, Mears and Velyvis 2003, Oransky and Tortora 2007), but long-term structural changes of the sacrum after fracture healing have not been explored.Our primary aim was to assess long-term radiological findings after surgically treated displaced sacral fractures. In addition, we wanted to assess whether pathological radiological findings, including bony structural changes of the sacrum, may contribute to neurological dysfunctions of the lower extremities or to the occurrence of pelvis-related pain. 相似文献50.
Mona Nysted Olav A Foss Jomar Klaksvik P?l Benum Kristin Haugan Otto Schnell Husby Arild Aamodt 《Acta orthopaedica》2014,85(2):152-158