Calcium Homeostatic Pathways Change with Gestation in Human Myometrium1

Abstract

A rise in intracellular calcium is the primary trigger for contractile activity in pregnant human myometrium. It is hypothesized that key proteins involved in myometrial calcium homeostasis are gestationally regulated and play an important role in the preparation for labor. The aims of the study were to investigate the role of sarcoplasmic reticulum Ca ATPases (SERCAs) in regulating spontaneous contractile activity in myometrium, and to determine the expression of SERCA isoforms 2a and 2b, and the plasma membrane Ca ATPase (PMCA), at term and during labor. Western blot analysis demonstrated that the expression of SERCA 2a and 2b significantly increased in myometrium of women in labor compared with those not in labor. The augmentation of contractile activity in laboring myometrium in the presence of a SERCA 2 inhibitor, cyclopiazonic acid (CPA), demonstrated the functional significance of this observation. It is interesting that the application of CPA in the presence of a calcium-activated potassium channel inhibitor to term nonlabor myometrium mimicked the response of myometrium from women in active labor to CPA alone. We conclude that the activity of SERCA isoforms becomes increasingly important in the maintenance of regular contractile activity during labor and may compensate for the functional loss of other calcium control pathways at term.

Hormonal signaling and signal pathway crosstalk in the control of myometrial calcium dynamics

“…1). PMCA has been detected in human myometrium and expression is reported to increase in labor [73]. PMCA1b, 4a and 4b mRNA/ or protein are detectable in rat uterus [74]; there is significant expression of PMCA1 and PMCA4b but not PMCA4a mRNA in human myometrial cells (Fig.…”

Regulation of Human Myometrial Contractility During Pregnancy and Labour: Are Calcium Homeostatic Pathways Important?

“…Functionally, CCE has been demonstrated in primary cultured myometrium (Tribe et al 2000b) and both CCE and non-CCE seem to be important in oxytocin-induced calcium responses measured in immortalised pregnant human myometrial cells (Monga et al 1999). The relevance of CCE and non-CCE to spontaneous or agonist-stimulated contractile activity has not been determined in human myometrium, although preliminary data from our laboratory suggests that capacitative calcium entry, stimulated by depletion of the cyclopiazonic acid (CPA)-sensitive calcium store, is sufficient to elicit a contraction in the presence of an L-type calcium channel blocker (Fig.…”

“…Indeed, we have recently identified a significant increase in the protein expression of two SERCA isoforms (SERCA 2a and SERCA 2b) and PMCA in myometrial tissue from women in labour compared with term non-labour. A greater functional role for SERCA isoforms in regulating contractile activity in myometrium from women in labour was also demonstrated (Tribe et al 2000b). The role of Na + -Ca 2+ exchange in governing contractile activity has not been studied in human myometrium, but studies in rats suggest that Na + -Ca 2+ exchange is more important for relaxation in spontaneous contracting myometrium from pregnant rats compared with non-pregnant rats (Taggart & Wray, 1997).…”

The Plasma Membrane Calcium ATPasesand Their Role as Major New Players in Human Disease

“…This switch in mode of Ca 2ϩ extrusion may be explained by an examination of the effects of physiological concentrations of oxytocin on human myometrium taken at term, which found the hormone to strongly inhibit Ca 2ϩ -ATPase activity and thus induce contraction (294), a phenomenon which has also been reciprocated at late stages of gestation in the rat (222). Surprisingly, oxytocin's inhibitory actions on PMCA and SERCA activity at term occur despite an increase in expression of both pumps in the human myometrium during active labor (374).…”