title: Thrombin Induces Inositol Trisphosphate-Mediated Spatially Extensive Responses in Lung Microvessels.
abstract: Activation of plasma membrane receptors initiates compartmentalized second messenger signaling. Whether this compartmentalization facilitates the preferential intercellular diffusion of specific second messengers is unclear. Toward this, the receptor-mediated agonist, thrombin, was instilled into microvessels in a restricted region of isolated blood-perfused mouse lungs. Subsequently, the thrombin-induced increase in endothelial F-actin was determined using confocal fluorescence microscopy. Increased F-actin was evident in microvessels directly treated with thrombin and in those located in adjoining thrombin-free regions. This increase was abrogated by inhibiting inositol trisphosphate-mediated calcium release with Xestospongin C (XeC). XeC also inhibited the thrombin-induced increase in the amplitude of endothelial cytosolic Ca2+oscillations. Instillation of thrombin and XeC into adjacent restricted regions increased F-actin in microvessels in the thrombin-treated and adjacent regions but not in those in the XeC-treated region. Thus, inositol trisphosphate, and not calcium, diffused interendothelially to the spatially remote thrombin-free microvessels. Thus, activation of plasma membrane receptors increased the ambit of inflammatory responses via a second messenger different from that used by stimuli that induce cell-wide increases in second messengers. Thrombin however failed to induce the spatially extensive response in microvessels of mice lacking endothelial connexin43, suggesting a role for connexin43 gap junctions. Compartmental second messenger signaling and interendothelial communication define the specific second messenger involved in exacerbating proinflammatory responses to receptor-mediated agonists.
authors.affiliation: Department of Physiology, The University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Rachel
authors.initials: R
authors.lastname: Escue
authors.affiliation: Department of Physiology, The University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Kathirvel
authors.initials: K
authors.lastname: Kandasamy
authors.affiliation: Department of Physiology, The University of Tennessee Health Science Center, Memphis, Tennessee. Electronic address: kparthas@uthsc.edu.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Parthasarathi
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D018031:Connexin 43 / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008168:Lung / Q000098:blood supply*; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D022502:Stress Fibers / Q000187:drug effects / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology*
chemical_list: D000199:Actins; D018031:Connexin 43; D053496:Inositol 1,4,5-Trisphosphate Receptors; D015544:Inositol 1,4,5-Trisphosphate; D013917:Thrombin; D002118:Calcium