Class C GPCRs in the airway

Patel, Brijeshkumar S.; Ravix, Jovanka; Pabelick, Christina M.; Prakash, Y. S.

doi:10.1016/j.coph.2020.04.002

Cited by 7 publications

(3 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The CaSR belongs to the Class C family of GPCRs that further include metabotropic GABA-B and glutaminergic receptors and a number of orphan receptors (Brauner-Osborne et al, 2007 ; Patel et al, 2020 ). The CaSR, GABA-B and glutaminergic receptors are the most explored in any tissue.…”

Section: Discussionmentioning

confidence: 99%

Calcium-Sensing Receptor Contributes to Hyperoxia Effects on Human Fetal Airway Smooth Muscle

et al. 2021

Self Cite

View full text Add to dashboard Cite

Supplemental O2 (hyperoxia), necessary for maintenance of oxygenation in premature infants, contributes to neonatal and pediatric airway diseases including asthma. Airway smooth muscle (ASM) is a key resident cell type, responding to hyperoxia with increased contractility and remodeling [proliferation, extracellular matrix (ECM) production], making the mechanisms underlying hyperoxia effects on ASM significant. Recognizing that fetal lungs experience a higher extracellular Ca2+ ([Ca2+]o) environment, we previously reported that the calcium sensing receptor (CaSR) is expressed and functional in human fetal ASM (fASM). In this study, using fASM cells from 18 to 22 week human fetal lungs, we tested the hypothesis that CaSR contributes to hyperoxia effects on developing ASM. Moderate hyperoxia (50% O2) increased fASM CaSR expression. Fluorescence [Ca2+]i imaging showed hyperoxia increased [Ca2+]i responses to histamine that was more sensitive to altered [Ca2+]o, and promoted IP3 induced intracellular Ca2+ release and store-operated Ca2+ entry: effects blunted by the calcilytic NPS2143. Hyperoxia did not significantly increase mitochondrial calcium which was regulated by CaSR irrespective of oxygen levels. Separately, fASM cell proliferation and ECM deposition (collagens but not fibronectin) showed sensitivity to [Ca2+]o that was enhanced by hyperoxia, but blunted by NPS2143. Effects of hyperoxia involved p42/44 ERK via CaSR and HIF1α. These results demonstrate functional CaSR in developing ASM that contributes to hyperoxia-induced contractility and remodeling that may be relevant to perinatal airway disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Calcium-Sensing Receptor Contributes to Hyperoxia Effects on Human Fetal Airway Smooth Muscle

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…These receptors have been identified as slow regulators of glutamate transmission [51]. While this pathway is extensively involved in neuronal signaling, these receptors are also expressed in the airway and are thought to play a role in bronchodilation and airway remodeling [52]. Several of these receptors have been implicated in nicotine addiction and may be targets for smoking cessation pharmacotherapies in the future [53].…”

Section: Discussionmentioning

confidence: 99%

Intrauterine Smoke Exposure, microRNA Expression during Human Lung Development, and Childhood Asthma

Rosenberg

Liu

Sharma

et al. 2023

IJMS

View full text Add to dashboard Cite

Intrauterine smoke (IUS) exposure during early childhood has been associated with a number of negative health consequences, including reduced lung function and asthma susceptibility. The biological mechanisms underlying these associations have not been established. MicroRNAs regulate the expression of numerous genes involved in lung development. Thus, investigation of the impact of IUS on miRNA expression during human lung development may elucidate the impact of IUS on post-natal respiratory outcomes. We sought to investigate the effect of IUS exposure on miRNA expression during early lung development. We hypothesized that miRNA–mRNA networks are dysregulated by IUS during human lung development and that these miRNAs may be associated with future risk of asthma and allergy. Human fetal lung samples from a prenatal tissue retrieval program were tested for differential miRNA expression with IUS exposure (measured using placental cotinine concentration). RNA was extracted and miRNA-sequencing was performed. We performed differential expression using IUS exposure, with covariate adjustment. We also considered the above model with an additional sex-by-IUS interaction term, allowing IUS effects to differ by male and female samples. Using paired gene expression profiles, we created sex-stratified miRNA–mRNA correlation networks predictive of IUS using DIABLO. We additionally evaluated whether miRNAs were associated with asthma and allergy outcomes in a cohort of childhood asthma. We profiled pseudoglandular lung miRNA in n = 298 samples, 139 (47%) of which had evidence of IUS exposure. Of 515 miRNAs, 25 were significantly associated with intrauterine smoke exposure (q-value < 0.10). The IUS associated miRNAs were correlated with well-known asthma genes (e.g., ORM1-Like Protein 3, ORDML3) and enriched in disease-relevant pathways (oxidative stress). Eleven IUS-miRNAs were also correlated with clinical measures (e.g., Immunoglobulin E andlungfunction) in children with asthma, further supporting their likely disease relevance. Lastly, we found substantial differences in IUS effects by sex, finding 95 significant IUS-miRNAs in male samples, but only four miRNAs in female samples. The miRNA–mRNA correlation networks were predictive of IUS (AUC = 0.78 in males and 0.86 in females) and suggested that IUS-miRNAs are involved in regulation of disease-relevant genes (e.g., A disintegrin and metalloproteinase domain 19 (ADAM19), LBH regulator of WNT signaling (LBH)) and sex hormone signaling (Coactivator associated methyltransferase 1(CARM1)). Our study demonstrated differential expression of miRNAs by IUS during early prenatal human lung development, which may be modified by sex. Based on their gene targets and correlation to clinical asthma and atopy outcomes, these IUS-miRNAs may be relevant for subsequent allergy and asthma risk. Our study provides insight into the impact of IUS in human fetal lung transcriptional networks and on the developmental origins of asthma and allergic disorders.

show abstract

“…CaSR is critical in regulating calcium hemostasis and maintains the extracellular Ca 2+ concentration within a tight range (1,2,17,55). Consequently, more than 400 different germline gain-and loss-offunction CaSR mutations have been found (32,56).…”

Section: Discussionmentioning

confidence: 99%

Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor

et al. 2021

View full text Add to dashboard Cite

Calcium-sensing receptor (CaSR) is a class C G protein–coupled receptor (GPCR) that plays an important role in calcium homeostasis and parathyroid hormone secretion. Here, we present multiple cryo–electron microscopy structures of full-length CaSR in distinct ligand-bound states. Ligands (Ca2+ and l-tryptophan) bind to the extracellular domain of CaSR and induce large-scale conformational changes, leading to the closure of two heptahelical transmembrane domains (7TMDs) for activation. The positive modulator (evocalcet) and the negative allosteric modulator (NPS-2143) occupy the similar binding pocket in 7TMD. The binding of NPS-2143 causes a considerable rearrangement of two 7TMDs, forming an inactivated TM6/TM6 interface. Moreover, a total of 305 disease-causing missense mutations of CaSR have been mapped to the structure in the active state, creating hotspot maps of five clinical endocrine disorders. Our results provide a structural framework for understanding the activation, allosteric modulation mechanism, and disease therapy for class C GPCRs.

show abstract

Class C GPCRs in the airway

Cited by 7 publications

References 76 publications

Calcium-Sensing Receptor Contributes to Hyperoxia Effects on Human Fetal Airway Smooth Muscle

Calcium-Sensing Receptor Contributes to Hyperoxia Effects on Human Fetal Airway Smooth Muscle

Intrauterine Smoke Exposure, microRNA Expression during Human Lung Development, and Childhood Asthma

Structural basis for activation and allosteric modulation of full-length calcium-sensing receptor

Contact Info

Product

Resources

About