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Molecular mechanisms controlling the tone of smooth muscle sphincters

Smooth muscle sphincters are ring-shaped structures encircling an opening or passage in hollow organs. These structures control the entrance or release of contents in these organs, mediating various biological functions essential for homeostasis. Physiologically, they often remain closed most of the time and open for a short period as needed. Defects in sphincters cause a variety of diseases, including gastroesophageal reflux disease and fecal/urinary incontinence. A central unsolved question in the field of smooth muscle has been how smooth muscle cells generate a spontaneous or basal tone to maintain sphincters in the contracted state. We have used internal anal sphincter (IAS) as a phenotype to understand the molecular mechanisms underlying the basal tone. Using combined techniques from molecular biology, biophysics, and physiology, we have established that the interplay of the RyR-TMEM16A and L-type voltage-dependent Ca2+ channel raises the intracellular Ca2+ concentration, leading to the activation of myosin light chain kinase and the generation and maintenance of IAS basal tone (Zhang et al., 2016). We use a state-of-the-art two-photon microscope to understand synchronized Ca2+ oscillations and asynchronized Ca2+ oscillations in IAS tissues (Lu et al., 2021).

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