How can activity be regulated in a spontaneously active tissue? This simple question underlies efforts to enable us to control uterine contractions, so that we can better help women suffering threatened pre-term labour or labouring dysfunctionally (inadequately) at term. The fact that the uterus is a myogenic smooth muscle, requiring neither nerves nor hormones to produce its rhythmic contractions, tells us that there is a powerful intrinsic mechanism that has to be understood, if we are going to be successful in regulating its activity. Activity in myometrial smooth muscle cells begins with a pacemaking depolarization and action potential firing. The mechanism of that pacemaker activity remains obscure. We recently reported the occurrence of interstitial cells of Cajal-live cells (ICCs) in rat uterus, but although capable of producing outward current, inward currents were not apparent, making them unlikely pacemakers (1). It may be more likely that a subset of myocytes, perhaps expressing a modified set of ion channels, and scattered throughout the uterus, act as pacemakers. We have for example found that around 30% of rat uterine myocytes express Ca-activated Cl channels and produce inward current (2). Spontaneous firing of action potentials and elevations of Ca can be observed in freshly isolated uterine myocytes. Selective targeting of these cells may become a future therapeutic goal. As Ca entry through L-type Ca channels is crucially important for uterine contractility, changes of channel activity will modify uterine activity. However because of their wide distribution in other tissues, there use is limited, although nifedipine remains a first choice tocolytic. We have investigated the role played by the internal Ca store, the sarcoplasmic reticulum (SR) in the uterus. The studies in animal and women’s uteri have led us to suggest that the SR does not play a major role in augmenting Ca for contraction, even during hormonal stimulation (3). Although in other smooth muscles a role for the SR in controlling excitability has been shown, via a Ca spark – BK (Ca-activated K channels, producing small outward current events , STOCs) (4), this remains unclear in the uterus. This is because Ca sparks are not produced (5) and although BK channels are expressed, their pharmacological inhibition e.g. with iberiotoxin or 1 mM tetraethyl ammonium, has little effect on uterine contractility. It may be that small conductance Ca-activated K channels (SK) have a role to play, but this is still being investigated . An additional mechanism for affecting signalling pathways in the uterus has recently been proposed – lipid microdomains known as rafts or caveolae (6). We have found that manipulation of rafts, through altering membrane cholesterol ( a key component of rafts), has a profound affect on Ca signalling and contractility, with increasing cholesterol being deleterious. (6). As elevated cholesterol is often associated with obesity, we have hypothesised that disturbance of lipid raft signalling mechanisms in obese women, may account for the increased number of caesarean sections for dysfunctional labour, found in this group (7). As oxytocin receptors have been found to also be affected by their lipid environment and working best in caveolae, and as caveolae numbers may be under oestrogenic control, new insights into how hormonal influence affects uterine activity may be gained.Reference 1 : Duquette RA et al (2005) Biol Reprod 72,276-282Reference 2 : Jones K et al (2004) Eur J Physiol 448,36-43Reference 3 : Wray S et al (2003) J Soc Gynecol Investig 10,252-64Reference 4 : Burdyga T & Wray S (2005) Nature 436,559-562Reference 5 : Burdyga T et al (2007) Ann.N.Y.Acad.Sci, in pressReference 6 : Noble K et al (2006) J Physiol 570,29-35