RhoA/Rho-Kinase: Pathophysiologic and Therapeutic Implications in Gastrointestinal Smooth Muscle Tone and Relaxation  Satish Rattan, Benjamin R. Phillips, Pinckney J. Maxwell  Gastroenterology  Volume 138, Issue 1, Pages 13-18.e3 (January 2010) DOI: 10.1053/j.gastro.2009.11.016 Copyright © 2010 AGA Institute Terms and Conditions

Figure 1 Schematic representation of the major pathways involved in excitation–contraction and relaxation coupling in GI smooth muscle. RhoA/ROCK may be activated either by G-protein–coupled receptor activation or independent of it. The complex of RhoA.GDI.GDP usually reflects inactive state of RhoA. It transforms via RhoGEFs into an active RhoA.GDI.GTP complex formation. GEFs catalyze the exchange of GDP for GTP on RhoA. RhoGAP drives the reaction in the reverse direction. Activated RhoA/ROCK leads to the phosphorylation of MLC20, and subsequent contraction via these different pathways. First, there is inhibition of MLCP through its regulatory subunit MYPT1. Second, there is phosphorylation of CPI-17 and subsequent inhibition of MLCP via its catalytic subunit PP1c. Finally, there is MLCK-like activity. Shown on the left side, RhoA/ROCK may either activate PKC directly or via phospholipase D1/PA/DAG. There is growing evidence in different smooth muscle systems that PKC may lie upstream of RhoA/ROCK pathway (bidirectional arrow). In contrast with the multiple pathways for the phosphorylation of MLC20 as in the case of RhoA/ROCK, the major target for the PKC is CPI-17. Interestingly, phosphorylation of CPI-17 is not limited to RhoA/ROCK and PKC, but other kinases, such as ZIP kinase, and ILK can mediate this event. Green arrows and substrates indicate stimulation; red lines and substrates indicate inhibition. *Hypothetical sites of up-regulation in the case to spontaneously tonic smooth muscle (eg, sphincteric) or during the pathologically hypercontractility state of different GI smooth muscles. Conversely, these sites may be inherently down-regulated in the case of phasic smooth muscle in the basal state or during the pathologically hypocontractility state. #Hypothetical sites of inherent down-regulation of the tonic smooth muscle and up-regulation of the phasic smooth muscle in the basal state. Abbreviations: GAP, GTPase-activating protein; ILK, integrin-linked kinase; Rho.GDI, guanine exchange dissociation inhibitor; Rho.GEF, GDT-GTP exchange factor; ROCK, Rho kinase; ZIPK, zipper-interacting kinase. Gastroenterology 2010 138, 13-18.e3DOI: (10.1053/j.gastro.2009.11.016) Copyright © 2010 AGA Institute Terms and Conditions