Abstract:
Jun kinase-induced overexpression
of leukemia-associated Rho GEF (LARG) mediates sustained
hypercontraction of longitudinal smooth muscle in inflammation.
Am J Physiol Cell Physiol 306: C1129?C1141, 2014. First
published April 16, 2014; doi:10.1152/ajpcell.00021.2014.?The signaling
pathways mediating sustained contraction of mouse colonic longitudinal
smooth muscle and the mechanisms involved in hypercontractility
of this muscle layer in response to cytokines and TNBS-induced
colitis have not been fully explored. In control longitudinal smooth
muscle cells, ACh acting via m3 receptors activated sequentially
G12, RhoGEF (LARG), and the RhoA/Rho kinase pathway. There
was abundant expression of MYPT1, minimal expression of CPI-17,
and a notable absence of a PKC/CPI-17 pathway. LARG expression
was increased in longitudinal muscle cells isolated from muscle strips
cultured for 24 h with IL-1 or TNF- or obtained from the colon of
TNBS-treated mice. The increase in LARG expression was accompanied
by a significant increase in ACh-stimulated Rho kinase and
ZIP kinase activities, and sustained muscle contraction. The increase
in LARG expression, Rho kinase and ZIP kinase activities, and
sustained muscle contraction was abolished in cells pretreated with
the Jun kinase inhibitor, SP600125. Expression of the MLCP activator,
telokin, and MLCP activity were also decreased in longitudinal
muscle cells from TNBS-treated mice or from strips treated with
IL-1 or TNF-. In contrast, previous studies had shown that sustained
contraction in circular smooth muscle is mediated by sequential
activation of G13, p115RhoGEF, and dual RhoA-dependent pathways
involving phosphorylation of MYPT1 and CPI-17. In colonic
circular smooth muscle cells isolated from TNBS-treated mice or
from strips treated with IL-1 or TNF-, CPI-17 expression and
sustained muscle contraction were decreased. The disparate changes
in the two muscle layers contribute to intestinal dysm