Inhibitory effects of calcitonin gene-related peptide on substance-P-induced superoxide production in human neutrophils.
We examined the mechanisms of the inhibitory effects of calcitonin gene-related peptide (CGRP) on substance-P-induced superoxide anion (O2-) production in human neutrophils. Substance P (30 microM) caused O2- production associated with an inositol-1,4,5-trisphosphate (IP3)-induced transient increase in intracellular Ca2+ concentrations ([Ca2+]i). CGRP (10 microM) significantly inhibited substance-P-induced O2- production and transient increase in [Ca2+]i, but it only slightly suppressed IP3 formation. In addition, CGRP inhibited IP3-induced O2- production and transient increase in [Ca2+]i, caused by exogenous addition of IP3 in saponin-permeabilized neutrophils. These findings suggest that CGRP inhibits the response of neutrophils to substance P through the inhibition of IP3-induced Ca2+ release from intracellular Ca2+ stores. The inhibitory effects of CGRP on substance P- or IP3-induced O2- production and increases in [Ca2+]i were abolished by pretreating the neutrophils with a CGRP receptor antagonist, CGRP-(8 - 37), or cyclic AMP (cAMP)-dependent protein kinase inhibitors, N-[2-(methylamino) ethyl]-5-isoquinoline-sulfonamide dihydrochloride (H-8) and 9-n-hexyl ester derivative of K-572a (8R, 9S, 11 S)-(--)-9-hydroxy-9-methoxycarbonyl-8-methyl-8-methyl-2,3,9,10- tetrahydro-8,11-epoxy-1H,8H, 11 H-2,7b,11a-triazadibenzo (a,g)cycloocta(cde)trinden-1-one (KT5720). We concluded that CGRP receptor stimulation reduces substance-P-induced O2- production by the inhibition of IP3-induced transient increase in [Ca2+]i, probably via the phosphorylation of IP3 receptor by cAMP-dependent protein kinase.
Tanabe
T
T
Department of Pharmacology, Kansai Medical University, Osaka, Japan.
Otani
H
H
Zeng
X T
XT
Mishima
K
K
Ogawa
R
R
Inagaki
C
C
D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism*; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism*
D013481:Superoxides; D013373:Substance P; D015544:Inositol 1,4,5-Trisphosphate; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium