A review of recent insights into the role of the sarcoplasmic reticulum and Ca entry in uterine smooth muscle

The uterine sacroplasmic reticulum (SR) takes up and stores calcium [Ca], using an ATPase (SERCA) and the Ca-buffering proteins, calsequestrin and calreticulin. This stored Ca can be released via IP3-gated Ca channels. Decreases in luminal Ca concentration [Ca] have been directly measured following agonist stimulation. During spontaneous contractions however, there appears to be no involvement of the SR, as Ca entry and efflux across the plasma membrane account for these phasic contractions. After over-viewing current knowledge concerning SR structure and function, we highlight three areas of research which suggest new ways of looking at the role of the SR in the uterus, although they may be controversial or speculative at the moment. Firstly, we review the evidence for the function, if any, of Ca-induced SR Ca release channels, the ryanodine receptor (RyR) and the lack of Ca sparks (the elemental release events from RyRs), in the uterus. Secondly, we ask does regulation of SERCA by the accessory protein, phospholamban, occur in the uterus and what is the effect of knocking out phospholamban on uterine activity? Thirdly, we address the question of when and how store-operated Ca entry occurs in the myometrium. By analogy with other, usually less excitable tissues, is there a mechanism that links store Ca depletion to plasma membrane Ca entry in smooth muscle cells within intact uterus and is it physiologically relevant and regulated? Are the recently described proteins ORAI and STIM-1 involved in uterine store-operated Ca entry? We end the review by integrating these new insights with previous data to present a new working model of the SR in the uterus.