Enhanced calcium signaling to bradykinin in airway smooth muscle from hyperresponsive inbred rats

Abstract

Inbred Fischer 344 rats display airway hyperresponsiveness (AHR) in vivo compared with the normoresponsive Lewis strain. Fischer AHR has been linked with increased airway smooth muscle (ASM) contraction ex vivo and enhanced ASM cell intracellular Ca(2+) mobilization in response to serotonin compared with Lewis. To determine the generality of this association, we tested whether bradykinin (BK) also stimulates greater contraction of Fischer airways and greater Ca(2+) mobilization in Fischer ASM cells. Explants of Fischer intraparenchymal airways constricted faster and to a greater degree in response to BK than Lewis airways. BK also evoked higher Ca(2+) transients in Fischer than in Lewis ASM cells. ASM cell B(2) receptor expression was similar between the two strains. BK activated both phosphatidylinositide-specific phospholipase C (PI-PLC) and phosphatidylcholine-specific PLC to mobilize Ca(2+) in Fischer and Lewis ASM cells. PI-PLC activity, as measured by inositol polyphosphate accumulation, was similar in the two strains. PKC inhibition with GF109203X, Go6973, or Go6983 attenuated BK-mediated Ca(2+) transients in Fischer cells, whereas GF109203X potentiated while Go6976 and Go6983 did not affect Ca(2+) transients in Lewis cells. Enhanced Ca(2+) mobilization in ASM cells can arise from variations in PKC and may be an important component of nonspecific, innate AHR.

Dissociation of FK506-Binding Protein 12.6 kD from Ryanodine Receptor in Bronchial Smooth Muscle Cells in Airway Hyperresponsiveness in Asthma

“…These observations are consistent with the findings reported by Tao and colleagues (27,28). Nevertheless, the mechanism for the modulation of calcium responses of BSMCs to inflammatory cytokines is largely unexplored.…”

“…These results indicate that cADPR does not contribute to airway inflammation-induced dissociation of FKBP12.6 from the RyR2. Ca 21 mobilization from SR in BSMCs in response to contractile agonists such as bradykinin or acetylcholine is an important component of smooth muscle contraction (12,28,30). When dissociated from FKBP12.6, the RyR2 calcium channel on the SR membrane has more opening probability and becomes sensitized to intracellular activator signals.…”

Inhibition of L-Type Cav1.2 Ca2+Channels by 2,(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) and 2-[1-(3-Dimethyl-aminopropyl)-5-methoxyindol-3-yl]-3-(1H-indol-3-yl) Maleimide (Gö6983)

“…In summary, the present study shows that both LY294002 and Gö6983 exhibit Ca 2ϩ antagonistic properties in the concentration range usually applied to selectively block PI3-K (Quignard et al, 2001;Northcott et al, 2002;Wang et al, 2002;Callaghan et al, 2004;McDowell et al, 2004) and PKC (Tao et al, 2003), respectively. Therefore, evidence of a functional coupling of the PI3-K signaling pathway to L-type Ca 2ϩ -channel activity is hampered by the inhibitory effects of the compounds LY294002 and Gö6983 on L-type Ca 2ϩ channels.…”

Bradykinin activates calcium-dependent potassium channels in cultured human airway smooth muscle cells

“…The signaling pathway underlying BK-induced currents in ASM cells is still uncertain. Several studies have shown that BK is a Gq/G 11 -coupled receptor agonist with the potential to couple to phosphatidylinositidespecific phospholipase C (PI-PLC) (45), phosphatidylcholine phospholipase C (PC-PLC) (37), or phospholipase D (36). Stimulation of PI-PLC will promote the production of the second messenger, IP 3 , which releases Ca 2ϩ from intracellular stores to the cytoplasm, and 1,2-diacylglycerol, which activates PKC.…”

“…Furthermore, ion channel activity is altered in ASM cells from rats with a hyperresponsive phenotype (45), in atrial myocytes grown in an altered extracellular matrix environment (49), in smooth muscle cells exposed to proinflammatory mediators (19), and following exposure to environmental toxins (52). K ϩ channels other than BKCa may thus assume greater importance in ASM cell function in the asthmatic airway, where the matrix environment is altered and inflammatory mediators abound.…”