Force generation and maintenance in smooth muscle sphincters

Sphincters are ring-shaped smooth muscle structures encircling an opening or passage in hollow organs. These structures control the entrance or release of contents in these organs, mediating a variety of biological functions essential for homeostasis. Physiologically, they remain closed for most of the time and open for a short period as needed, and defects in sphincters cause a variety of diseases including gastroesophageal reflux disease and fecal/urinary incontinence. A major unsolved question in the field of smooth muscle has been how smooth muscle cells generate spontaneous tone to maintain sphincters in the contracted state. We have used internal anal sphincter (IAS) as a phenotype to understand the molecular mechanisms underlying this tone. We recently found that the interplay of the RyR-TMEM16A and L-type voltage-dependent Ca²⁺ channel (VDCC) raises the intracellular Ca²⁺ concentration, leading to the activation of myosin light chain kinase and the generation and maintenance of IAS tone (Figure 3). We are studying how sustained or prolonged Ca²⁺ signals in IAS smooth muscle cells are generated, whether the RyR-TMEM16A-VDCC pathway is an essential component of the rectoanal inhibitory reflex (RAIR) during defecation, and whether dysfunction in this pathway contributes to fecal incontinence.

Figure 3. The interplay among RyR, TMEM16A and L-type Ca2+ channel sets basal tone generation in IAS.