MAPKs represent novel therapeutic targets for gastrointestinal motility disorders

Figure 1 Conventional mechanisms of smooth muscle contraction. Smooth muscle contraction is primarily governed by the phosphorylation of the regulatory light chain (LC₂₀) of myosin II which is in turn driven by the balance between protein kinases responsible for phosphorylation of LC₂₀ and protein phosphatases responsible for its dephosphorylation. Ca²⁺ sensitization of contractile force can result from the direct phosphorylation of LC₂₀ by Ca²⁺-independent protein kinases and/or inhibition of myosin phosphatase activity by Ca²⁺-independent protein kinases. CPI-17: protein kinase C-potentiated inhibitory protein for protein phosphatase 1 of 17 kDa; ILK: integrin-linked kinase; LC₂₀: 20 kDa myosin light chain; MLCK: myosin light chain kinase; MYPT1: myosin targeting subunit 1 of myosin light chain phosphatase; M20: a 20 kDa non-catalytic subunit of myosin light chain phosphatase; PKC: protein kinase C; PP-1: catalytic subunit of protein phosphatase type-1; ROK: Rho-activated protein kinase; ZIPK: zipper-interacting protein kinase.

Figure 2 Proposed mechanisms by which ERK1/2 and p38MAPK signaling pathways contribute to smooth muscle contraction. MAPK pathways play important roles in modulating the contractile responses of normal and inflamed intestinal smooth muscles. MAPKs can alter the contractile activity of smooth muscle by (1) increasing the Mg²⁺-ATPase activity of myosin II, (2) phosphorylating caldesmon, a thin-filament associated protein, and promoting actin-myosin cross-bridges (3) phosphorylating HSP27 to reverse the inhibitory effects of caldesmon, or (4) directly regulating of myosin phosphatase activity. CPI-17: protein kinase C-potentiated inhibitory protein for protein phosphatase 1 of 17 kDa; ERK1/2: extracellular signal-regulated kinase 1/2; HSP27: phosphorylate heat shock protein; MAPKAPK-2: MAPK-activated protein kinase 2; LC₂₀: 20 kDa myosin light chain; MLCK: myosin light chain kinase; MLCP: myosin light chain phosphatase; p38MAPK: p38 mitogen-activated protein kinase; PKC: protein kinase C; ROK: Rho-activated protein kinase; ZIPK: zipper-interacting protein kinase.