{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T17:42:42Z","timestamp":1785519762764,"version":"3.56.0"},"reference-count":39,"publisher":"American Physiological Society","issue":"7","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Gastrointestinal and Liver Physiology"],"published-print":{"date-parts":[[2012,4,1]]},"abstract":"<jats:p>The knowledge of molecular control mechanisms underlying the basal tone in the intact human internal anal sphincter (IAS) is critical for the pathophysiology and rational therapy for a number of debilitating rectoanal motility disorders. We determined the role of RhoA\/ROCK and PKC pathways by comparing the effects of ROCK- and PKC-selective inhibitors Y 27632 and G\u00f6 6850 (10<jats:sup>\u22128<\/jats:sup>to 10<jats:sup>\u22124<\/jats:sup>M), respectively, on the basal tone in the IAS vs. the rectal smooth muscle (RSM). Western blot studies were performed to determine the levels of RhoA\/ROCK II, PKC-\u03b1, MYPT1, CPI-17, and MLC<jats:sub>20<\/jats:sub>in the unphosphorylated and phosphorylated forms, in the IAS vs. RSM. Confocal microscopic studies validated the membrane distribution of ROCK II. Finally, to confirm a direct relationship, we examined the enzymatic activities and changes in the basal IAS tone and p-MYPT1, p-CPI-17, and p-MLC<jats:sub>20<\/jats:sub>, before and after Y 27632 and G\u00f6 6850. Data show higher levels of RhoA\/ROCK II and related downstream signal transduction proteins in the IAS vs. RSM. In addition, data show a significant correlation between the active RhoA\/ROCK levels, ROCK enzymatic activity, downstream proteins, and basal IAS tone, before and after ROCK inhibitor. From these data we conclude 1) RhoA\/ROCK and downstream signaling are constitutively active in the IAS, and this pathway (in contrast with PKC) is the critical determinant of the basal tone in intact human IAS; and 2) RhoA and ROCK are potential therapeutic targets for a number of rectoanal motility disorders for which currently there is no satisfactory treatment.<\/jats:p>","DOI":"10.1152\/ajpgi.00430.2011","type":"journal-article","created":{"date-parts":[[2012,1,13]],"date-time":"2012-01-13T05:58:19Z","timestamp":1326434299000},"page":"G664-G675","source":"Crossref","is-referenced-by-count":28,"title":["RhoA\/ROCK pathway is the major molecular determinant of basal tone in intact human internal anal sphincter"],"prefix":"10.1152","volume":"302","author":[{"given":"Satish","family":"Rattan","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Gastroenterology and Hepatology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, 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