PubMed · 5454772
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J C Low, J M Earll. 1970-10-01. Calcium in toothpaste.. https://doi.org/10.1056/nejm197010012831417
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The CC chemokine receptor 3 (CCR3) plays an important role in the regulation of the migration of eosinophils, a leukocyte population involved in many inflammatory pathologies including asthma. CCR3 binds to the CC chemokine eotaxin, a promigratory cytokine originally isolated as the key component in a model of eosinophil-induced airway inflammation. We show here that eotaxin/CCR3 binding interactions exhibit a marked sensitivity to relatively small changes in the extracellular environment. In particular, modest variations in the pH and the level of sodium chloride over a range of physiologic and near physiologic conditions had dramatic effects on eotaxin binding and CCR3-mediated cytoplasmic Ca2+ mobilization. These biochemical indices were reflected at the functional level as well; small changes in pH and salt also resulted in striking changes in the migration of primary human eosinophils in vitro. These results reveal that relatively small perturbations in extracellular buffer conditions can yield widely disparate interpretations of CCR3 ligand binding and affinities and suggest that modulation of the tissue microenvironment might be utilized to control the affinity and efficacy of chemokine-mediated cell migration.
Desensitization and recovery of the inositol 1,4,5-trisphosphate (IP3) and intracellular free calcium concentration ([Ca2+]i) responses to thyrotropin-releasing hormone (TRH) were measured in HEK293 cells stably expressing the G protein-coupled TRH receptor. TRH caused a large, rapid, and transient increase in IP3 and a biphasic increase in [Ca2+]i. Desensitization of the TRH response was measured by exposing cells to TRH, washing, and then incubating the cells in hormone-free medium before reintroducing TRH and measuring IP3, [Ca2+]i, and intracellular Ca2+ pool size. When cells were incubated with 1 microM TRH for 10 s or 10 min and reexposed to TRH, there was almost no IP3 or [Ca2+]i increase. The IP3 response recovered first, followed by the [Ca2+]i response. The ionomycin-releasable intracellular Ca2+ pool was almost completely depleted by TRH, and pool refilling was slow. Thrombin, endothelin, and carbachol, when combined, stimulated large increases in IP3 and [Ca2+]i, but did not block the IP3 or [Ca2+]i responses to TRH measured 10 min later. In contrast, cells exposed to TRH first responded to combined agonists with a nearly normal increase in IP3, but no rise in [Ca2+]i. Thus, the IP3 response to TRH displays homologous desensitization, whereas the [Ca2+]i response displays heterologous desensitization because depletion of intracellular Ca2+ pools prevents responses to other hormones.
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