Abstract:
:1. Bradykinin has multiple effects on differentiated NG108-15 neuroblastoma x glioma cells: it increases Ins(1,4,5)P3 production and intracellular Ca2+ concentration [Ca2+]i evokes a Ca2+ activated K+ current (IK(Ca)) and inhibits M current (IM). We studied the effect of the aminosteroid U73122 and the antibiotic neomycin, both putative blockers of phospholipase C (PLC), on these four bradykinin effects. 2. Preincubation with 1 or 5 microM U73122 for 15 min partly suppressed Ins(1,4,5)P3 generation and the increase in [Ca2+]i induced by 1 microM bradykinin. U73122 10 microM caused total and irreversible inhibition. The inactive analogue U73343 was without effect. 3. Resting levels of Ins(1,4,5)P3 were not affected. However, resting [Ca2+]i was increased by 10 microM U73122, but not by U73343. Individual cells responded to 10 microM U73122 with a small increase in [Ca2+]i, followed in some cells by a large further rise. 4. Pretreatment of whole-cell clamped cells with 1 microM U73122 for 30 min reduced the bradykinin-induced IK(Ca) to a fifth of its normal size. To suppress it totally, a 7-12 min pretreatment with 5 microM U73122 was required. Again, U73343 was without effect. 5. U73122 and U73343 at concentrations of 5-10 microM irreversibly decreased the holding current (Ih) which at a holding potential of -30 or -20 mV mainly flows through open M channels. The decrease was often preceded by a transient increase. 6. M current (IM) measured with 1 s pulses, was also decreased by 5-10 microM U73122 and U73343, but short applications of U73122 could cause a small increase. The bradykinin-induced inhibition of IM was not affected by U73122. 7. Preincubation with 1 or 3 mM neomycin for 15 min did not affect Ins(1,4,5)P3 generation and the increase in [Ca2+]i induced by bradykinin. Pretreatment with 3 mM neomycin for about 20 min diminished the bradykinin-induced IK(Ca) to a fifth of its normal size. 8. The four main conclusions drawn from the results are: (a) U73122 suppresses bradykinin-induced PLC activation and IK(Ca), but not IM inhibition. (b) This indicates that the transient outward current IK(Ca), but not the decrease of IM in response to bradykinin, is mediated by PLC. (c) U73122 itself inhibits IM and mobilizes Ca2+ from intracellular stores. (d) Externally applied neomycin is not an effective inhibitor of PLC-mediated signalling pathways in NG108-15 cells.
journal_name
Br J Pharmacoljournal_title
British journal of pharmacologyauthors
Hildebrandt JP,Plant TD,Meves Hdoi
10.1038/sj.bjp.0700991subject
Has Abstractpub_date
1997-03-01 00:00:00pages
841-50issue
5eissn
0007-1188issn
1476-5381journal_volume
120pub_type
杂志文章abstract:BACKGROUND AND PURPOSE:Mast cells are important in allergic reactions. Here, we assessed the anti-allergic effects of the anti-cancer drug tozasertib specifically regarding regulatory effects on mast cell activation. EXPERIMENTAL APPROACH:Tozasertib effects on mast cell degranulation were determined by measuring β-hex...
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