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Functional role of muscarinic receptor subtypes in calcium sensitization and their contribution to rho-kinase and protein kinase C pathways in contraction of human detrusor smooth muscle.

Abstract

OBJECTIVE
We investigated the role of muscarinic receptor subtypes in calcium sensitization and their contribution to rho-kinase (ROK) and protein kinase C (PKC) pathways in carbachol (CCh)-induced contraction of human detrusor smooth muscle (DSM).
MATERIALS AND METHODS
α-toxin-permeabilized human DSM strips were prepared and mounted horizontally to record isometric force. The roles of M(2) and M(3) muscarinic receptors in Ca(2+) sensitization were studied using selective antagonists of M(2) (AF-DX116) and M(3) (4-DAMP) receptor subtypes. The effects of a selective inhibitor of ROK, Y-27632, and a selective inhibitor of PKC, bisindolylmaleimide I (GF-109203X), were also studied on contraction induced by 10 μM CCh with 100 μM guanosine triphosphate at a fixed 1 μM [Ca(2+)](i) after preincubation with 1 μM AF-DX116 or 1 μM 4-DAMP.
RESULTS
Carbachol-induced Ca(2+) sensitization was predominantly inhibited by 4-DAMP compared with AF-DX116. Four-DAMP equivalently inhibited the relaxation effect of 5 μM GF-109203X as well as that of 5 μM Y-27632 on CCh-induced Ca(2+) sensitization. AF-DX116 reduced the relaxation effect of Y-27632 to a greater degree than GF-109203X.
CONCLUSION
The results of the present study have demonstrated the predominant role of M(3) receptor subtype in Ca(2+) sensitization and the relative contribution to ROK and PKC pathways. Our study also shows that the ROK pathway is dominant compared with the PKC pathway after M(2) receptor activation, which in turn is inferior, but not negligible, in producing Ca(2+) sensitization.

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  • Publisher Full Text

    • Authors

    Shahab N, Kajioka S, Seki N, Naito S

    Institution

    Department of Urology, Faculty of Medicine and Health Sciences, Syarif Hidayatullah State Islamic University Jakarta, Indonesia.

    Source

    Urology 79:5 2012 May pg 1184.e7-13

    MeSH

    Amides
    Calcium
    Carbachol
    Enzyme Inhibitors
    Humans
    Indoles
    Maleimides
    Muscarinic Antagonists
    Muscle Contraction
    Muscle Relaxants, Central
    Muscle Relaxation
    Muscle, Smooth
    Parasympatholytics
    Piperidines
    Pirenzepine
    Protein Kinase C
    Pyridines
    Receptor, Muscarinic M2
    Receptor, Muscarinic M3
    Signal Transduction
    Urinary Bladder
    rho-Associated Kinases

    Pub Type(s)

    In Vitro
    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22546411