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BACKGROUND & AIMS: The regulatory subunit of myosin light chain phosphatase, MYPT1, has been proposed to control smooth muscle contractility by regulating phosphorylation of the Ca2+-dependent myosin regulatory light chain. We generated mice with a smooth muscle-specific deletion of MYPT1 to investigate its physiologic role in intestinal smooth muscle contraction. METHODS: We used the CreloxP system to establish Mypt1-floxed mice, with the promoter region and exon 1 of Myptl flanked by 2 loxP sites. These mice were crossed with SMA-Cre transgenic mice to generate mice with smooth muscle-specific deletion of MYPT1 (Mypt1SMKO mice). The phenotype was assessed by histologic, biochemical, molecular, and physiologic analyses. RESULTS: Young adult Mypt1SMKO mice had normal intestinal motility in vivo, with no histologic abnormalities. On stimulation with KC1 or acetylcholine, intestinal smooth muscles isolated from Mypt1SMKO mice produced robust and increased sustained force due to increased phosphorylation of the myosin regulatory light chain compared with muscle from control mice. Additional analyses of contractile properties showed reduced rates of force development and relaxation, and decreased shortening velocity, compared with muscle from control mice. Permeable smooth muscle fibers from Mypt1SMKO mice had increased sensitivity and contraction in response to Ca2+. Ca2+. CONCLUSIONS: MYPT1 is not essential for smooth muscle function in mice but regulates the Ca2+ sensitivity of force development and contributes to intestinal phasic contractile phenotype. Altered contractile responses in isolated tissues could be compensated by adaptive physiologic responses in vivo, where gut motility is affected by lower intensifies of smooth muscle stimulation for myosin phosphorylation and force development. [ABSTRACT FROM AUTHOR]