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HORMONES AND SIGNALING

Signaling pathways mediating gastrointestinal smooth muscle contraction and MLC₂₀ phosphorylation by motilin receptors

Departments of Physiology and Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Virginia

Submitted 12 July 2004 ; accepted in final form 30 August 2004

The signaling cascades initiated by motilin receptors in gastric and intestinal smooth muscle cells were characterized. Motilin bound with high affinity (IC₅₀ 0.7 ± 0.2 nM) to receptors on smooth muscle cells; the receptors were rapidly internalized via G protein-coupled receptor kinase 2 (GRK2). Motilin selectively activated G_q and G₁₃, stimulated G_q-dependent phosphoinositide (PI) hydrolysis and 1,4,5-trisphosphate (IP₃)-dependent Ca²⁺ release, and increased cytosolic free Ca²⁺. PI hydrolysis was blocked by expression of G_q minigene and augmented by overexpression of dominant negative RGS4(N88S) or GRK2(K220R). Motilin induced a biphasic, concentration-dependent contraction (EC₅₀ = 1.0 ± 0.2 nM), consisting of an initial peak followed by a sustained contraction. The initial Ca²⁺-dependent contraction and myosin light-chain (MLC)₂₀ phosphorylation were inhibited by the PLC inhibitor U-73122 and the MLC kinase inhibitor ML-9 but were not affected by the Rho kinase inhibitor Y27632 or the PKC inhibitor bisindolylmaleimide. Sustained contraction and MLC₂₀ phosphorylation were RhoA dependent and mediated by two downstream messengers: PKC and Rho kinase. The latter was partly inhibited by expression of G_q or G₁₃ minigene and abolished by coexpression of both minigenes. Sustained contraction and MLC₂₀ phosphorylation were partly inhibited by Y27632 and bisindolylmaleimide and abolished by a combination of both inhibitors. The inhibition reflected phosphorylation of two MLC phosphatase inhibitors: CPI-17 via PKC and MYPT1 via Rho kinase. We conclude that motilin initiates a G_q-mediated cascade involving Ca²⁺/calmodulin activation of MLC kinase and transient MLC₂₀ phosphorylation and contraction as well as a sustained G_q- and G₁₃-mediated, RhoA-dependent cascade involving phosphorylation of CPI-17 by PKC and MYPT1 by Rho kinase, leading to inhibition of MLC phosphatase and sustained MLC₂₀ phosphorylation and contraction.

interdigestive gut hormone; Rho kinase; G protein signaling

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