Role of the sarcoplasmic reticulum in uterine smooth muscle

The sarcoplasmic reticulum (SR) is present as an extensive network in uterine cells. In this chapter we examine its functional importance, relating in particular, to the control of contractility in pregnancy. The uterine SR has both ryanodine receptors (RyR) and inositol-1,4,5-trisphosphate InsP₃ receptors (InsP₃R). The RyR and subsequent Ca²⁺-induced Ca²⁺ release play little role in either human or rat contractions or Ca²⁺ transients. There may be subtle, spatiotemporal effects at the single cell level. Caffeine, an agonist for RyR fails to release Ca²⁺ and indeed produces relaxation not contraction. InsP₃ clearly causes release of Ca²⁺ from the uterine SR and an increase in force, although these changes are only small and transient compared to those occurring due to external Ca²⁺ entry. Inhibition of the SR Ca-ATPase by cyclopiazonic acid, empties Ca²⁺ from the SR. This is associated with an augmentation of force and Ca²⁺ transient. Thus the SR normally functions in the uterus to limit, not increase contractions. The mechanism may involve vectoral release of Ca²⁺ from the SR and activation of surface membrane K⁺ channels. This activation would tend to decrease L-type Ca²⁺ entry and hence reduce contraction. Thus the SR is playing a role in controlling membrane excitability and hence contractility. The SR also plays a role in the relaxation of force. This is not primarily due to a direct sequestering of large amounts of Ca²⁺, but rather that the SR directs Ca²⁺ to the surface membrane extrusion mechanisms, i.e. Ca-ATPase and Na⁺/Ca²⁺ exchanger. This enables them to act more efficiently, and therefore aids relaxation. Recent direct measurements of SR luminal content show decreases with agonist application but not during spontaneous activity; confirming the results described above. This technique will be used to better characterize the uterine SR, its control and relevance to normal and abnormal labours.