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OtherENDOCRINE PHARMACOLOGY

Mechanisms of Bradykinin-Induced Insulin Secretion in Clonalbeta Cell Line RINm5F

Chi Yang, Bumsup Lee, Ter-Hsin Chen and Walter H. Hsu
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1247-1252;
Chi Yang
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Bumsup Lee
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Ter-Hsin Chen
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Walter H. Hsu
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Abstract

We investigated the mechanisms underlying bradykinin (BK)-induced rise in intracellular Ca++ concentration [Ca++]i and insulin secretion using clonal beta cell line RINm5F. Incubation with a range of concentrations of BK increased in concentration-dependent manners both insulin secretion (BK of 10 nM to 10 μM) and [Ca++]i (BK of 100 nM to 100 μM). In Ca++-containing medium, BK (1 μM) induced a biphasic [Ca++]i rise, which was characterized by a Ca++ peak and a sustained Ca++ phase. In the Ca++-free medium, BK failed to increase insulin secretion and induced only a Ca++ peak without the sustained Ca++ phase. Thapsigargin (1 μM), an inhibitor of the Ca++ pump in the endoplasmic reticulum, abolished the Ca++ peak and the sustained phase. Nimodipine (1 μM), a voltage-dependent Ca++ channel blocker, abolished the BK-induced sustained Ca++ phase and inhibited BK-induced insulin release. The BK1 receptor agonist des-Arg9-BK (1 μM) did not change either [Ca++]i or insulin secretion. Both the BK-induced insulin secretion and rise in [Ca++]i were inhibited by a selective BK2 receptor antagonist, HOE 140 (3.3–100 nM), in concentration-dependent manners but were not by a BK1 receptor antagonist des-Arg9,Leu8-BK (1 μM). Pretreatment with pertussis toxin (0.1 μg/ml) did not block the BK-induced insulin secretion or increase in [Ca++]i. U-73122 (4, 6 and 8 μM), a phospholipase C inhibitor, antagonized both the BK-induced insulin secretion and the increase in [Ca++]i in a concentration-dependent and parallel manner. BK increased intracellular concentrations of inositol-1,4,5-trisphosphate (IP3). Neither (p-amylcinnamoyl)anthranilic acid (100 μM), a phospholipase A2 inhibitor, nor NG-nitro-l-arginine methylester (100 μM), a nitric oxide synthase inhibitor, inhibited these effects of BK. Taken together, these findings suggested that in betacells, BK activates BK2 receptors, which, in turn, activate a pertussis toxin-insensitive G protein. The G protein couples to phospholipase C, which promotes the formation of IP3 and diacylglycerol. IP3releases [Ca++]i from the intracellular Ca++ store, probably the endoplasmic reticulum, which triggers Ca++ influxvia voltage-dependent Ca++ channels and thus increases insulin secretion.

Footnotes

  • Send reprint requests to: Dr. Walter H. Hsu, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011.

  • ↵1 This work was partially supported by National Science Council, ROC(NSC86-2313-B-005-113-T).

  • ↵2 C. Yang, B. Lee, T.-H. Chen and W. H. Hsu, unpublished obervations.

  • Abbreviations:
    ACA
    (p-amylcinnamoyl)anthranilic acid
    AM
    acetoxymethyl ester
    BK
    bradykinin
    DAG
    diacylglycerol
    ER
    endoplasmic reticulum
    HOE 140
    IP3, inositol-1,4,5-trisphosphate
    KRB
    Krebs-Ringer bicarbonate solution
    L-NAME
    NG-nitro-l-arginine methylester
    PIP2
    phosphatidylinositol-4,5-bisphosphate
    PTX
    pertussis toxin
    PLA2
    phospholipase A2
    PLC
    phospholipase C
    TG
    thapsigargin
    VDCC
    voltage-dependent Ca++ channel
    • Received September 3, 1996.
    • Accepted May 12, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherENDOCRINE PHARMACOLOGY

Mechanisms of Bradykinin-Induced Insulin Secretion in Clonalbeta Cell Line RINm5F

Chi Yang, Bumsup Lee, Ter-Hsin Chen and Walter H. Hsu
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1247-1252;

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OtherENDOCRINE PHARMACOLOGY

Mechanisms of Bradykinin-Induced Insulin Secretion in Clonalbeta Cell Line RINm5F

Chi Yang, Bumsup Lee, Ter-Hsin Chen and Walter H. Hsu
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1247-1252;
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