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Browsing by Subject "Desensitization"
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Item G protein–coupled receptor interactions with arrestins and GPCR kinases: The unresolved issue of signal bias(Elsevier, 2022) Chen, Qiuyan; Tesmer, John J. G.; Biochemistry and Molecular Biology, School of MedicineG protein-coupled receptor (GPCR) kinases (GRKs) and arrestins interact with agonist-bound GPCRs to promote receptor desensitization and downregulation. They also trigger signaling cascades distinct from those of heterotrimeric G proteins. Biased agonists for GPCRs that favor either heterotrimeric G protein or GRK/arrestin signaling are of profound pharmacological interest because they could usher in a new generation of drugs with greatly reduced side effects. One mechanism by which biased agonism might occur is by stabilizing receptor conformations that preferentially bind to GRKs and/or arrestins. In this review, we explore this idea by comparing structures of GPCRs bound to heterotrimeric G proteins with those of the same GPCRs in complex with arrestins and GRKs. The arrestin and GRK complexes all exhibit high conformational heterogeneity, which is likely a consequence of their unusual ability to adapt and bind to hundreds of different GPCRs. This dynamic behavior, along with the experimental tactics required to stabilize GPCR complexes for biophysical analysis, confounds these comparisons, but some possible molecular mechanisms of bias are beginning to emerge. We also examine if and how the recent structures advance our understanding of how arrestins parse the "phosphorylation barcodes" installed in the intracellular loops and tails of GPCRs by GRKs. In the future, structural analyses of arrestins in complex with intact receptors that have well-defined native phosphorylation barcodes, such as those installed by the two nonvisual subfamilies of GRKs, will be particularly illuminating.Item Improving CPAP Adherence for Obstructive Sleep Apnea: A Practical Application Primer on CPAP Desensitization(2020) Chernyak, YelenaIntroduction: Obstructive sleep apnea (OSA) is a common medical condition with well-established morbidity and mortality. Continuous positive airway pressure (CPAP) is a highly effective treatment prescribed to most individuals with OSA that has documented poor adherence rate for a variety of reasons including claustrophobia and discomfort. CPAP desensitization is an effective, simple, and brief treatment shown to improve adherence rates to CPAP. Methods: A psychologist specializing in behavioral sleep medicine developed this module focused on teaching medical residents the techniques of CPAP desensitization. The educational activity was an interactive 45-minute seminar which included a didactic component followed by a case presentation and interactive role-play. A post-seminar survey was used to evaluate the content of the workshop, as well as growth in awareness and perception of knowledge and skills with a pre- to post-workshop evaluation. Results: In a survey of 25 primary care and psychiatry residents and sleep medicine fellows, 92% of respondents indicated that the topic of CPAP barriers and CPAP desensitization was important. Ratings of self-reported knowledge and skills improved nearly one-third following the workshop. Qualitative feedback indicated the utility and enthusiasm learners had for this topic. Discussion: The workshop on CPAP desensitization was a valuable tool that should be disseminated more widely to improve treatment adherence in the significant portion of the population that suffers from OSA which does not use adherence to positive airway pressure therapy. The workshop is applicable to other health professionals including medical students and nursing, social work, or psychology trainees.Item Methimazole Desensitization in a 4-Year-Old With Refractory Graves Disease(Elsevier, 2021-02-20) Schneider Aguirre, Rebecca; Khalid, Ariba; Ismail, Heba M.; Nabhan, Zeina; Pediatrics, School of MedicineObjective: To describe a 4-year-old girl with Graves disease and methimazole allergy who underwent desensitization, allowing continued methimazole use when other treatments were contraindicated. Methods: We formulated a desensitization plan utilizing cetirizine and prednisone for a patient with previously diagnosed Graves disease who developed urticaria and arthralgias from methimazole. She was admitted for monitoring of rash, urticaria, angioedema, and anaphylaxis. Her methimazole dose was increased as tolerated and then titrated as an outpatient. Results: A 4-year-old girl presented with a heart rate of 195 beats/minute, blood pressure of 145/108, and subsequent labs of undetectable thyroid stimulating hormone (TSH), free T4 5.8 ng/dL, thyroid peroxidase antibody 11.5 IU/ml, and TSH receptor antibody 39.03 IU/L, consistent with Graves disease. She developed urticaria and arthralgias after 2.5 weeks on methimazole, which resolved with drug cessation. Because of her age, the risks of radioactive iodine ablation and surgery were concerning; therefore, methimazole desensitization was attempted. Prednisone (1 mg/kg/day) and cetirizine (5 mg/day) were started prior to low-dose methimazole reintroduction and continued for 7 days. Methimazole was then gradually increased to a final dose of 15 mg daily (0.8 mg/kg/day). Free T4 normalized within a month (1.12 ng/dL), and her TSH normalized within 10 months (4.61 mcU/mL). Except for 2 possible breakthrough allergic responses that resolved with pulse steroids, she continues to tolerate methimazole. Conclusion: We describe a case of methimazole desensitization. In this patient, pretreatment with prednisone, coupled with daily cetirizine, successfully induced methimazole tolerance when other treatment modalities were contraindicated.Item S-nitrosylation is required for β2AR desensitization and experimental asthma(Elsevier, 2022) Fonseca, Fabio V.; Raffay, Thomas M.; Xiao, Kunhong; McLaughlin, Precious J.; Qian, Zhaoxia; Grimmett, Zachary W.; Adachi, Naoko; Wang, Benlian; Hausladen, Alfred; Cobb, Brian A.; Zhang, Rongli; Hess, Douglas T.; Gaston, Benjamin; Lambert, Nevin A.; Reynolds, James D.; Premont, Richard T.; Stamler, Jonathan S.; Pediatrics, School of MedicineThe β2-adrenergic receptor (β2AR), a prototypic G-protein-coupled receptor (GPCR), is a powerful driver of bronchorelaxation, but the effectiveness of β-agonist drugs in asthma is limited by desensitization and tachyphylaxis. We find that during activation, the β2AR is modified by S-nitrosylation, which is essential for both classic desensitization by PKA as well as desensitization of NO-based signaling that mediates bronchorelaxation. Strikingly, S-nitrosylation alone can drive β2AR internalization in the absence of traditional agonist. Mutant β2AR refractory to S-nitrosylation (Cys265Ser) exhibits reduced desensitization and internalization, thereby amplifying NO-based signaling, and mice with Cys265Ser mutation are resistant to bronchoconstriction, inflammation, and the development of asthma. S-nitrosylation is thus a central mechanism in β2AR signaling that may be operative widely among GPCRs and targeted for therapeutic gain.Item Tailoring Dental Appointments for Neurodivergent Children(2025-05) Chelmella, Payton; Van Antwerp, Leah; Department of Occupational Therapy, School of Health and Human Sciences; Steele, JaimeMany neurodivergent children have a difficult time during their dental visits or cannot find a dental office willing to treat them. This doctoral capstone project aimed to give a local pediatric dentist office the information and experience they need to confidently provide care for neurodivergent patients and patients with dental anxiety. Six evidence-based themes about beneficial adaptations and modifications were addressed, including: acclimating to the dentist, desensitization, patient care beyond the chair, child behavior management, adaptive communication, and sensory processing. The capstone student provided the dental team with additional information during the project, but the above themes were emphasized the most. The dental team members completed a pre-survey (9 participants) and post-survey (8 participants) to evaluate their knowledge and confidence in three areas: general knowledge about adaptations and modifications, perceived knowledge about concepts relating to specific adaptations and modifications, and their confidence in implementing specific adaptations and modifications. The results show that the three categories had a statistically significant difference between pre-survey and post-survey results with a medium to large effect size. This project had a strong impact on the dental team’s knowledge and confidence in ways to treat their neurodivergent patients and patients with dental anxiety, therefore, this project shows that occupational therapy has a valuable place in pediatric dental settings.